Tetrahydrobenzindolone derivatives

ABSTRACT

Compounds represented by the following formula (I) or pharmaceutically acceptable salts thereof and a process for producing the same are disclosed. The compounds have progesterone receptor binding inhibitory activity and, hence, can be used as therapeutic and prophylactic agents for progesterone-related diseases. Specifically, they are useful as carcinostatic agents for breast cancer and ovarian cancer, therapeutic agents for hysteromyoma, endometriosis, meningioma, and myeloma, abortifacients, oral contraceptive pills, and therapeutic and prophylactic agents for osteoporosis and climacteric disturbance. ##STR1## wherein R 1  represents alkyl or aralkyl; R 2  represents a hydrogen atom, alkylcarbonyl, cycloalkylcarbonyl, aromatic acyl, heteroaromatic acyl, saturated heterocyclic acyl, alkyl, alkenyl, aralkyl, carbamoyl, alkylcarbamoyl, aromatic carbamoyl, aralkylcarbamoyl, alkylaminocarbonyl, cycloalkylcarbamoyl, alkoxycarbonyl, aryloxycarbonyl, heteroaromatic thiocarbonyl, saturated heterocyclic thiocarbonyl, or alkyl-thiocarbamoyl: and R 3  represents a hydrogen atom, a hydroxyl group, alkyloxy, alkylcarbonyloxy, alkylthio, or arylthio.

This application is a 371 of PCT/JP97/04683 filed Dec. 18, 1997.

BACKGROUND OF THE INVENTION

1. Field of Invention

The present invention relates to compounds as a progesterone receptorbinding inhibotor and pharmaceutical compositions containing the same.

2. Background Art

In recent years, even in Japan, the number of patients suffering frombreast cancer has increased, and it is foreseen that the number of thepatients suffering from breast cancer would become largest among themalignant tumors in women in the 21st century. Ovariectomy has for thefirst time been used as endocrinotherapy for breast cancer. Thereafter,adrenalectomy and hypophysectomy have been reported to be useful astherapy for breast cancer in progress, and, since then, surgicalendocrinotherapy has been mainly used and made progress. In the surgicalendocrinotherapy, an organ involved in the secretion of estrogen isremoved to regress estrogen dependent breast cancer. This, however,results in loss of not only estrogen but also life-sustaining hormones,including steroid hormones, posing many problems associated with thequality of life.

Non-steroidal anti-estrogen agents typified by Tamoxifen Citrate whichappeared in the latter half of 1970s have extensively used clinically byvirtue of high effect against breast cancer and much lower side effectthan conventional androgen and estrogen. Then, they have replaced thesurgical endocrinotherapy used as main therapy for breast cancer.

More recently, agents having a new mechanism of action, such asmedroxyprogesterone acetate (MPA) ("NYUGAN NO RINSHO", vol. 1, 201-213(1986)), aromatase inhibitor, luteinizing hormone-releasing hormone(LH-RH) agonist ("GAN TO KAGAKU RYOHO", 16, 2729 (1994)) have beendeveloped, resulting in diversified endocrinotherapy for breast cancer.

Further, in recent years, the treatment of breast cancer with anantiprogesterone agent based on progesterone receptor has been activelyattempted. For example, Mifepristone (RU38486) (Cancer Res.), 49,2851-2856, 1989, Onapristone (ZK98299) (J. Steroid Biochem. Molecu.Biol., 41, 339-348, 1992) and the like are under development. Thesenovel types of agents as a progesterone receptor binding inhibotor areexpected to be useful for the treatment of not only breast cancer butalso for endometriosis, hysteromyoma, meningioma and the like. Further,side effects, attributable to weak estrogenagonist action which aredeveloped by prolonged administration of Tamoxifen Citrate, such asendometrioma, thrombosis, and hepatoma, and, in addition, cancerresistant to Tamoxifen Citrate, have been reported as a new problem.Since antiprogesterone agents are different from Tamoxifen Citrate inmechanism of action, they are expected as novel therapeutic agents whichcan avoid the above problems.

However, all of them have a steroidal skeleton. Thus, they have beenpointed out to have side effect characteristic of steroid. Therefore, inorder to overcome these problems, an agent having progesterone receptorbinding inhibitory activity without the steroid skeleton has beendesired in the art.

Some of the present inventors have previously succeeded in isolation ofsubstance PF1092, which, despite a non-steroid skeleton, is a inhibitoragainst binding of progesterone to progesterone receptor, from acultured mixture of a strain belonging to the genus Penicillium(Japanese Patent Laid-Open No. 253467/1996 and EP722940A, which areincorporated herein by reference).

The substance PF1092 is a ligularenolide type sesquiterpene having inits molecule an enol lactone ring structure. Many sesquiterpenes eachhaving in its molecule an oxygen atom derived from a lactone ringstructure or a furan ring structure are known in the art.

To the best of the present inventors' knowledge, no ligularenolide typeskeleton containing a hetero atom, other than an oxygen atom,independently of natural and non-natural types are known in the art.

SUMMARY OF THE INVENTION

The present inventors have conducted the synthesis of a novel compound,having a ligularenolide type skeleton, analogous to PF1092 and theconfirmation of the activity thereof. As a result, they have found thatthese compounds have highly selective progesterone receptor bindinginhibitory activity and better stability than compounds having aligularenolide skeleton. The present invention has been made based onsuch finding.

Accordingly, an object of the present invention is to provide novelcompounds which have a ligularenolide skeleton as highly selectiveprogesterone receptor binding inhibitor.

Another object of the present invention is to provide therapeutic andprophylactic agents for progesterone-related diseases.

A further object of the present invention is to provide intermediateswhich may be preferably used for the synthesis of the novel compounds.

Thus, according to one aspect of the present invention, there isprovided a compound represented by the following formula (I) or apharmaceutically acceptable salt thereof: ##STR2## wherein R¹ represents

a hydrogen atom,

optionally substituted C₁ -C₁₀ alkyl,

optionally substituted C₂ -C₁₀ alkenyl,

optionally substituted C₂ -C₁₀ alkynyl,

optionally substituted C₃ -C₁₀ cycloalkyl, or

optionally substituted C₇ -C₁₅ aralkyl;

R² represents

a hydrogen atom,

optionally substituted C₁ -C₁₀ alkylcarbonyl,

optionally substituted C₂ -C₁₀ alkenylcarbonyl,

optionally substituted C₂ -C₁₀ alkynylcarbonyl,

optionally substituted C₃ -C₁₅ cycloalkylcarbonyl,

optionally substituted C₇ -C₁₅ aralkylcarbonyl,

optionally substituted C₇ -C₁₅ aromatic acyl,

optionally substituted C₂ -C₁₅ heteroaromatic acyl having at least onehetero atom selected from the group consisting of nitrogen, oxygen, andsulfur atoms,

optionally substituted C₃ -C₁₅ saturated heterocyclic acyl having atleast one hetero atom selected from the group consisting of nitrogen,oxygen, and sulfur atoms,

optionally substituted C₁ -C₁₀ alkyl,

optionally substituted C₂ -C₁₀ alkenyl,

optionally substituted C₂ -C₁₀ alkynyl,

optionally substituted C₃ -C₁₀ cycloalkyl,

optionally substituted C₇ -C₁₅ aralkyl, carbamoyl,

optionally substituted N-C₁ -C₁₀ alkylcarbamoyl,

optionally substituted N-C₆ -C₁₅ aromatic carbamoyl,

optionally substituted N-C₇ -C₁₅ aralkylcarbamoyl,

optionally substituted N,N-di-C₁ -C₁₀ alkylaminocarbonyl,

optionally substituted N-C₃ -C₁₀ cycloalkylcarbamoyl,

optionally substituted C₁ -C₁₀ alkoxycarbonyl,

optionally substituted C₆ -C₁₅ aryloxycarbonyl,

optionally substituted C₇ -C₁₅ aralkyloxycarbonyl,

optionally substituted C₁ -C₁₅ heteroaromatic thiocarbonyl having atleast one hetero atom selected from the group consisting of nitrogen,oxygen, and sulfur atoms,

optionally substituted C₂ -C₁₅ saturated heterocyclic thiocarbonylhaving at least one hetero atom selected from the group consisting ofnitrogen, oxygen, and sulfur atoms, or

optionally substituted N-C₁ -C₁₀ alkyl-thiocarbamoyl; and

R³ represents

a hydrogen atom,

a hydroxyl group,

optionally substituted C₁ -C₁₀ alkyloxy,

optionally substituted C₂ -C₁₀ alkenyloxy,

optionally substituted C₂ -C₁₀ alkynyloxy,

optionally substituted C₃ -C₁₀ cycloalkyloxy,

optionally substituted C₇ -C₁₅ aralkyloxy,

optionally substituted C₁ -C₁₀ alkylcarbonyloxy,

optionally substituted C₂ -C₁₀ alkenylcarbonyloxy,

optionally substituted C₂ -C₁₀ alkynylcarbonyloxy,

optionally substituted C₃ -C₁₀ cycloalkylcarbonyloxy,

optionally substituted C₇ -C₁₅ aromatic acyloxy,

optionally substituted C₇ -C₁₅ aralkylcarbonyloxy,

optionally substituted C₁ -C₁₀ alkylthio,

optionally substituted C₂ -C₁₀ alkenylthio,

optionally substituted C₂ -C₁₀ alkynylthio,

optionally substituted C₃ -C₁₀ cycloalkylthio,

optionally substituted C₆ -C₁₅ arylthio, or

optionally substituted C₇ -C₁₅ aralkylthio.

According to another aspect of the present invention, there is provideda pharmaceutical composition, useful as a therapeutic or prophylacticagent for progesterone-related diseases, as an abortifacient, or as acontraceptive, comprising the compound as an active ingredient.

According to a further aspect of the present invention, there isprovided a compound, useful as an intermediate for the synthesis of thecompound represented by formula (I), represented by the followingformula (II) or a pharmaceutically acceptable salt thereof: ##STR3##wherein R¹ represents

a hydrogen atom,

optionally substituted C₁ -C₁₀ alkyl,

optionally substituted C₂ -C₁₀ alkenyl,

optionally substituted C₂ -C₁₀ alkynyl,

optionally substituted C₃ -C₁₀ cycloalkyl, or

optionally substituted C₇ -C₁₅ aralkyl.

BRIEF DESCRIPTION OF THE DRAWINGS

The FIGURE is a diagram showing the results of a test on the chemicalstability of the compound according to the present invention, whereincompound (a) is the compound prepared in Example 24 and compound (b) is3β-hydroxy-2α-methoxy-1(10),7(11),8-eremophilatrien-12,8-olide which isa compound provided by replacing the nitrogen atom in the compound (a)with an oxygen atom. In this test, an aqueous NaOH solution was added tomethanol solutions of these respective compounds, and the amount of thecompounds remaining undecomposed was measured with the elapse of time.

DETAILED DESCRIPTION OF THE INVENTION

Definition

As used herein, the terms "alkyl," "alkenyl," and "alkynyl" as a groupor a part of a group respectively mean straight or branched chain alkyl,alkenyl, and alkynyl. The term "halogen atom" used herein means afluorine, chlorine, bromine, or iodine atom. The term "aralkyl" usedherein means benzyl, phenylethyl (phenethyl), methylbenzyl,naphthylmethyl or the like. The term "acyl" used herein meansalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aralkylcarbonyl,cycloalkylcarbonyl, aromatic acyl, heteroaromatic acyl, or saturatedheterocyclic acyl. The term "aryl" preferably means phenyl, naphthyl,tolyl or the like.

Compounds Represented by Formula (I)

In the formula (I), the C₁ -C₁₀ alkyl represented by R¹ and R² ispreferably C₁ -C₆ alkyl, more preferably C₁ -C₅ alkyl.

At least one hydrogen atom on the alkyl may be substituted, and examplesof substituents usable herein include a halogen atom, nitro, amino, C₁-C₆ alkyl disubstituted (for example, dimethyl-substituted) amino,carboxyl, C₁ -C₆ alkoxy (for example, methoxy), C₁ -C₆alkoxy-substituted C₁ -C₆ alkoxy, a hydroxyl group, sulfoxyl, C₁ -C₆alkylthio (for example, methylthio), mercapto, C₁ -C₆ alkylsulfonyl (forexample, methylsulfonyl), cyano, phenyl, C₃ -C₁₀ cycloalkyl (preferablyC₃ -C₇ cycloalkyl, for example, cyclopropyl), oxiranyl, 2-propenyl, andhydroxyiminomethyl. The C₁ -C₆ alkyl in the optional substituentdescribed-above and described-below represented by R¹, R², and R³ ispreferably C₁ -C₄ alkyl.

The C₂ -C₁₀ alkenyl represented by R¹ and R² is preferably C₂ -C₆alkenyl, more preferably C₂ -C₄ alkenyl.

At least one hydrogen atom on the alkenyl may be substituted, andexamples of substituents usable herein include a halogen atom, nitro,amino, C₁ -C₆ alkyl disubstituted (for example, dimethyl-substituted)amino, carboxyl, C₁ -C₆ alkoxy (for example, methoxy), a hydroxyl group,sulfoxyl, C₁ -C₆ alkylthio (for example, methylthio), mercapto, C₁ -C₆alkylsulfonyl (for example, methylsulfonyl), cyano, phenyl, C₃ -C₁₀cycloalkyl (preferably C₃ -C₇ cycloalkyl, for example, cyclopropyl),oxiranyl, 2-propenyl, and hydroxyiminomethyl.

The C₂ -C₁₀ alkynyl represented by R¹ and R is preferably C₂ -C₆alkynyl, more preferably C₂ -C₄ alkynyl.

At least one hydrogen atom on the alkynyl may be substituted, andexamples of substituents usable herein include a halogen atom, nitro,amino, C₁ -C₆ alkyl disubstituted (for example, dimethyl-substituted)amino, carboxyl, C₁ -C₆ alkoxy (for example, methoxy), a hydroxyl group,sulfoxyl, C₁ -C₆ alkylthio (for example, methylthio), mercapto, C₁ -C₆alkylsulfonyl (for example, methylsulfonyl), cyano, phenyl, C₃ -C₁₀cycloalkyl (preferably C₃ -C₇ cycloalkyl, for example, cyclopropyl),oxiranyl, 2-propenyl, and hydroxyiminomethyl.

The C₃ -C₁₀ cycloalkyl represented by R¹ and R² is preferably C₃ -C₇cycloalkyl, and examples thereof include cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

At least one hydrogen atom on the cycloalkyl may be substituted, andexamples of substituents usable herein include a halogen atom, nitro,amino, C₁ -C₆ alkyl disubstituted (for example, dimethyl-substituted)amino, carboxyl, C₁ -C₆ alkoxy (for example, methoxy), C₁ -C₆alkoxy-substituted C₁ -C₆ alkoxy, a hydroxyl group, sulfoxyl, C₁ -C₆alkylthio (for example, methylthio), mercapto, C₁ -C₆ alkylsulfonyl (forexample, methylsulfonyl), cyano, phenyl, C₃ -C₁₀ cycloalkyl (preferablyC₃ -C₇ cycloalkyl, for example, cyclopropyl), oxiranyl, 2-propenyl, andhydroxyiminomethyl.

Examples of the C₇ -C₁₅ aralkyl represented by R¹ and R² include benzyl,phenylethyl, methylbenzyl, and naphthylmethyl.

At least one hydrogen atom on the aralkyl (preferably a hydrogen atom onthe ring) may be substituted, and examples of substituents usable hereininclude C₁ -C₆ alkyl, a halogen atom, nitro, amino, C₁ -C₆ alkyldisubstituted (for example, dimethyl-substituted) amino, carboxyl, C₁-C₆ alkoxy (for example, methoxy), a hydroxyl group, sulfoxyl, C₁ -C₆alkylthio (for example, methylthio), mercapto, cyano, phenyl, and C₃-C₁₀ cycloalkyl (preferably C₃ -C₇ cycloalkyl, for example,cyclopropyl).

The C₁ -C₁₀ alkylcarbonyl represented by R² is preferably C₁ -C₆alkylcarbonyl, more preferably C₁ -C₄ alkylcarbonyl.

At least one hydrogen atom on the alkylcarbonyl may be substituted, andexamples of substituents usable herein include a halogen atom, nitro,amino, C₁ -C₆ alkyl disubstituted (for example, dimethyl-substituted)amino, carboxyl, C₁ -C₆ alkoxy (for example, methoxy), a hydroxyl group,sulfoxyl, C₁ -C₆ alkylthio (for example, methylthio), mercapto, C₁ -C₆alkylsulfonyl (for example, methylsulfonyl), cyano, phenyl, C₃ -C₁₀cycloalkyl (preferably C₃ -C₇ cycloalkyl, for example, cyclopropyl),oxiranyl, 2-propenyl, and hydroxyiminomethyl.

The C₂ -C₁₀ alkenylcarbonyl represented by R² is preferably C₂ -C₆alkenylcarbonyl, more preferably C₂ -C₄ alkenylcarbonyl.

At least one hydrogen atom on the alkenylcarbonyl may be substituted,and examples of substituents usable herein include a halogen atom,nitro, amino, C₁ -C₆ alkyl disubstituted (for example,dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (for example,methoxy), a hydroxyl group, sulfoxyl, C₁ -C₆ alkylthio (for example,methylthio), mercapto, C₁ -C₆ alkylsulfonyl (for example,methylsulfonyl), cyano, phenyl, C₃ -C₁₀ cycloalkyl (preferably C₃ -C₇cycloalkyl, for example, cyclopropyl), oxiranyl, 2-propenyl, andhydroxyiminomethyl.

The C₂ -C₁₀ alkynylcarbonyl represented by R² is preferably C₂ -C₆alkynylcarbonyl, more preferably C₂ -C₄ alkynylcarbonyl.

At least one hydrogen atom on the alkynylcarbonyl may be substituted,and examples of substituents usable herein include a halogen atom,nitro, amino, C₁ -C₆ alkyl disubstituted (for example,dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (for example,methoxy), a hydroxyl group, sulfoxyl, C₁ -C₆ alkylthio (for example,methylthio), mercapto, C₁ -C₆ alkylsulfonyl (for example,methylsulfonyl), cyano, phenyl, C₃ -C₁₀ cycloalkyl (preferably C₃ -C₇cycloalkyl, for example, cyclopropyl), oxiranyl, 2-propenyl, andhydroxyiminomethyl.

The C₃ -C₁₀ cycloalkylcarbonyl represented by R² is preferably C₃ -C₇cycloalkylcarbonyl, and examples thereof include cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, and cyclohexylcarbonyl.

At least one hydrogen atom on the cycloalkylcarbonyl may be substituted,and examples of substituents usable herein include a halogen atom,nitro, amino, C₁ -C₆ alkyl disubstituted (for example,dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (for example,methoxy), a hydroxyl group, sulfoxyl, C₁ -C₆ alkylthio (for example,methylthio), mercapto, C₁ -C₆ alkylsulfonyl (for example,methylsulfonyl), cyano, phenyl, C₃ -C₁₀ cycloalkyl (preferably C₃ -C₇cycloalkyl, for example, cyclopropyl), oxiranyl, 2-propenyl, andhydroxyiminomethyl.

Examples of the C₆ -C₁₅ aromatic acyl represented by R² include benzoyl,toluoyl, and naphthoyl.

At least one hydrogen atom on the aromatic acyl may be substituted, andexamples of substituents usable herein include C₁ -C₆ alkyl, a halogenatom (a chlorine, bromine, or iodine atom), nitro, amino, C₁ -C₆ alkyldisubstituted (for example, dimethyl-substituted) amino, carboxyl, C₁-C₆ alkoxy (for example, methoxy), a hydroxyl group, sulfoxyl, C₁ -C₆alkylthio (for example, methylthio), mercapto, C₁ -C₆ alkylsulfonyl (forexample, methylsulfonyl), cyano, phenyl, and C₃ -C₁₀ cycloalkyl(preferably C₃ -C₇ cycloalkyl, for example, cyclopropyl), oxiranyl,2-propenyl, and hydroxyiminomethyl.

Examples of the C₇ -C₁₅ aralkylcarbonyl represented by R² includebenzylcarbonyl, phenylethylcarbonyl, methylbenzylcarbonyl, andnaphthylmethylcarbonyl.

At least one hydrogen atom on the aralkylcarbonyl may be substituted,and examples of substituents usable herein include C₁ -C₆ alkyl, ahalogen atom, nitro, amino, C₁ -C₆ alkyl disubstituted (for example,dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (for example,methoxy), a hydroxyl group, sulfoxyl, C₁ -C₆ alkylthio (for example,methylthio), mercapto, cyano, phenyl, and C₃ -C₁₀ cycloalkyl (preferablyC₃ -C₇ cycloalkyl, for example, cyclopropyl).

The C₂ -C₁₅ heteroaromatic acyl, having at least one hetero atomselected from the group consisting of nitrogen, oxygen, and sulfuratoms, represented by R² is preferably a five- or six-memberedheteroaromatic acyl having one or two nitrogen, oxygen, or sulfur atoms(for example, furoyl, pyranylcarbonyl, thenoyl, or imidazolylcarbonyl),or a five- or six-membered heteroaromatic acyl containing a nitrogenatom and a sulfur atom (for example, thiazolylcarbonyl). Theheteroaromatic ring of the heteroaromatic acyl may be condensed withother ring, for example, a benzene ring, and examples of theheteroaromatic ring condensed with other ring include benzothiophene.

At least one hydrogen atom on the heteroaromatic acyl may besubstituted, and examples of substituents usable herein include C₁ -C₆alkyl, a halogen atom, nitro, amino, C₁ -C₆ alkyl disubstituted (forexample, dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (forexample, methoxy), a hydroxyl group, sulfoxyl, C₁ -C₆ alkylthio (forexample, methylthio), mercapto, C₁ -C₆ alkylsulfonyl (for example,methylsulfonyl), cyano, phenyl, and C₃ -C₁₀ cycloalkyl (preferably C₃-C₇ cycloalkyl, for example, cyclopropyl), oxiranyl, 2-propenyl, andhydroxyiminomethyl.

The C₃ -C₁₅ saturated heterocyclic acyl, having at least one hetero atomselected from the group consisting of nitrogen, oxygen, and sulfuratoms, represented by R² is preferably a five- or six-memberedheterocyclic acyl containing one oxygen or sulfur atom (for example,pyrrolidinylcarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, ormorpholinylcarbonyl).

At least one hydrogen atom on the saturated heterocyclic acyl may besubstituted, and examples of substituents usable herein include C₁ -C₆alkyl, a halogen atom, nitro, amino, C₁ -C₆ alkyl disubstituted (forexample, dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (forexample, methoxy), a hydroxyl group, sulfoxyl, C₁ -C₆ alkylthio (forexample, methylthio), mercapto, C₁ -C₆ alkylsulfonyl (for example,methylsulfonyl), cyano, phenyl, and C₃ -C₁₀ cycloalkyl (preferably C₃-C₇ cycloalkyl, for example, cyclopropyl), oxiranyl, 2-propenyl, andhydroxyiminomethyl.

The carbamoyl represented by R² is N,N-dihydrocarbamoyl having nosubstituent.

The N-C₁ -C₁₀ alkylcarbamoyl represented by R² is preferably N-C₁ -C₆alkylcarbamoyl, more preferably N-C₁ -C₄ alkylcarbamoyl.

At least one hydrogen atom on the alkylcarbamoyl may be substituted, andexamples of substituents usable herein include a halogen atom, nitro,amino, C₁ -C₆ alkyl disubstituted (for example, dimethyl-substituted)amino, carboxyl, C₁ -C₆ alkoxy (for example, methoxy), C₁ -C₆alkoxy-substituted C₁ -C₆ alkoxy, a hydroxyl group, sulfoxyl, C₁ -C₆alkylthio (for example, methylthio), mercapto, C₁ -C₆ alkylsulfonyl (forexample, methylsulfonyl), cyano, phenyl, and C₃ -C₁₀ cycloalkyl(preferably C₃ -C₇ cycloalkyl, for example, cyclopropyl), oxiranyl,2-propenyl, and hydroxyiminomethyl.

The N,N-di-C₁ -C₁₀ alkylaminocarbonyl represented by R² is preferablyN,N-di-C₁ -C₆ alkylaminocarbonyl, more preferably N,N-di-C₁ -C₄alkylaminocarbonyl.

The N-C₃ -C₁₀ cycloalkylcarbamoyl represented by R² is preferably N-C₃-C₇ cycloalkylcarbamoyl, and examples thereof includeN-cyclopropylcarbamoyl, N-cyclobutylcarbamoyl, N-cyclopentylcarbamoyl,and N-cyclohexylcarbamoyl.

At least one hydrogen atom on the N-cycloalkylcarbamoyl may besubstituted, and examples of substituents usable herein include ahalogen atom, nitro, amino, C₁ -C₆ alkyl disubstituted (for example,dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (for example,methoxy), C₁ -C₆ alkoxy-substituted C₁ -C₆ alkoxy, a hydroxyl group,sulfoxyl, C₁ -C₆ alkylthio (for example, methylthio), mercapto, C₁ -C₆alkylsulfonyl (for example, methylsulfonyl), cyano, phenyl, and C₃ -C₁₀cycloalkyl (preferably C₃ -C₇ cycloalkyl, for example, cyclopropyl),oxiranyl, 2-propenyl, and hydroxyiminomethyl.

Examples of the N-C₆ -C₁₅ aromatic carbamoyl represented by R² includeN-phenylcarbamoyl, N-toluylcarbamoyl, and N-naphthylcarbamoyl.

At least one hydrogen atom on the N-aromatic carbamoyl may besubstituted, and examples of substituents usable herein include C₁ -C₆alkyl, a halogen atom, nitro, amino, C₁ -C₆ alkyl disubstituted (forexample, dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (forexample, methoxy), a hydroxyl group, sulfoxyl, C₁ -C₆ alkylthio (forexample, methylthio), mercapto, C₁ -C₆ alkylsulfonyl (for example,methylsulfonyl), cyano, phenyl, and C₃ -C₁₀ cycloalkyl (preferably C₃-C₇ cycloalkyl, for example, cyclopropyl), oxiranyl, 2-propenyl, andhydroxyiminomethyl.

Examples of the N-C₇ -C₁₅ aralkylcarbamoyl represented by R² includeN-benzylcarbamoyl, N-phenylethylcarbamoyl, N-methylbenzylcarbamoyl, andN-naphthylmethylcarbamoyl.

At least one hydrogen atom on the N-aralkylcarbamoyl may be substituted,and examples of substituents usable herein include C₁ -C₆ alkyl, ahalogen atom, nitro, amino, C₁ -C₆ alkyl disubstituted (for example,dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (for example,methoxy), a hydroxyl group, sulfoxyl, C₁ -C₆ alkylthio (for example,methylthio), mercapto, cyano, phenyl, and C₃ -C₁₀ cycloalkyl (preferablyC₃ -C₇ cycloalkyl, for example, cyclopropyl).

The C₁ -C₁₀ alkoxycarbonyl represented by R² is preferably C₁ -C₆alkoxycarbonyl, more preferably C₁ -C₄ alkoxycarbonyl.

At least one hydrogen atom on the alkoxy may be substituted, andexamples of substituents usable herein include a halogen atom, nitro,amino, C₁ -C₆ alkyl disubstituted (for example, dimethyl-substituted)amino, carboxyl, C₁ -C₆ alkoxy (for example, methoxy), C₁ -C₆alkoxy-substituted C₁ -C₆ alkoxy, a hydroxyl group, sulfoxyl, C₁ -C₆alkylthio (for example, methylthio), mercapto, C₁ -C₆ alkylsulfonyl (forexample, methylsulfonyl), cyano, phenyl, and C₃ -C₁₀ cycloalkyl(preferably C₃ -C₇ cycloalkyl, for example, cyclopropyl), oxiranyl,2-propenyl, and hydroxyiminomethyl.

Examples of the C₇ -C₁₅ aryloxycarbonyl represented by R₂ includephenyloxycarbonyl, toluyloxycarbonyl, and naphthyloxycarbonyl.

At least one hydrogen atom on the aryloxycarbonyl may be substituted,and examples of substituents usable herein include C₁ -C₆ alkyl, ahalogen atom, nitro, amino, C₁ -C₆ alkyl disubstituted (for example,dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (for example,methoxy), a hydroxyl group, sulfoxyl, C₁ -C₆ alkylthio (for example,methylthio), mercapto, C₁ -C₆ alkylsulfonyl (for example,methylsulfonyl), cyano, phenyl, and C₃ -C₁₀ cycloalkyl (preferably C₃-C₇ cycloalkyl, for example, cyclopropyl), oxiranyl, 2-propenyl, andhydroxyiminomethyl.

Examples of the C₈ -C₁₅ aralkyloxycarbonyl represented by R² includebenzyloxycarbonyl, phenylethyloxycarbonyl, methylbenzyloxycarbonyl, andnaphthylmethyloxycarbonyl.

At least one hydrogen atom on the aralkyloxycarbonyl may be substituted,and examples of substituents usable herein include C₁ -C₆ alkyl, ahalogen atom, nitro, amino, C₁ -C₆ alkyl disubstituted (for example,dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (for example,methoxy), a hydroxyl group, sulfoxyl, C₁ -C₆ alkylthio (for example,methylthio), mercapto, cyano, phenyl, and C₃ -C₁₀ cycloalkyl (preferablyC₃ -C₇ cycloalkyl, for example, cyclopropyl).

The C₁ -C₁₅ heteroaromatic thiocarbonyl, having at least one hetero atomselected from the group consisting of nitrogen, oxygen, and sulfuratoms, represented by R² is preferably a five-membered or six-memberedheteroaromatic thiocarbonyl having one oxygen or sulfur atom (forexample, imidazolylthiocarbonyl).

At least one hydrogen atom on the heteroaromatic thiocarbonyl may besubstituted, and examples of substituents usable herein include C₁ -C₆alkyl, a halogen atom, nitro, amino, C₁ -C₆ alkyl disubstituted (forexample, dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (forexample, methoxy), a hydroxyl group, sulfoxyl, C₁ -C₆ alkylthio (forexample, methylthio), mercapto, C₁ -C₆ alkylsulfonyl (for example,methylsulfonyl), cyano, phenyl, and C₃ -C₁₀ cycloalkyl (preferably C₃-C₇ cycloalkyl, for example, cyclopropyl), oxiranyl, 2-propenyl, andhydroxyiminomethyl.

The C₂ -C₁₅ saturated heterocyclic thiocarbonyl, having at least onehetero atom selected from the group consisting of nitrogen, oxygen, andsulfur atoms, represented by R² is preferably a five-membered orsix-membered saturated heterocyclic thiocarbonyl having one oxygen orsulfur atom (for example, pyrrolidyl-thiocarbonyl,piperidyl-thiocarbonyl, piperazyl-thiocarbonyl, morpholyl-thiocarbonyl).

At least one hydrogen atom on the saturated heterocyclic thiocarbonylmay be substituted, and examples of substituents usable herein includeC₁ -C₆ alkyl, a halogen atom, nitro, amino, C₁ -C₆ alkyl disubstituted(for example, dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (forexample, methoxy), a hydroxyl group, sulfoxyl, C₁ -C₆ alkylthio (forexample, methylthio), mercapto, C₁ -C₆ alkylsulfonyl (for example,methylsulfonyl), cyano, phenyl, and C₃ -C₁₀ cycloalkyl (preferably C₃-C₇ cycloalkyl, for example, cyclopropyl), oxiranyl, 2-propenyl, andhydroxyiminomethyl.

The C₁ -C₁₀ alkyl-thiocarbamoyl represented by R² is preferably C₁ -C₆alkyl-thiocarbamoyl, more preferably N-C₁ -C₄ alkyl-thiocarbamoyl.

At least one hydrogen atom on the alkyl-thiocarbamoyl may besubstituted, and examples of substituents usable herein include ahalogen atom, nitro, amino, C₁ -C₆ alkyl disubstituted (for example,dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (for example,methoxy), C₁ -C₆ alkoxy-substituted C₁ -C₆ alkoxy, a hydroxyl group,sulfoxyl, C₁ -C₆ alkylthio (for example, methylthio), mercapto, C₁ -C₆alkylsulfonyl (for example, methylsulfonyl), cyano, phenyl, and C₃ -C₁₀cycloalkyl (preferably C₃ -C₇ cycloalkyl, for example, cyclopropyl),oxiranyl, 2-propenyl, and hydroxyiminomethyl.

The C₁ -C₁₀ alkyloxy represented by R³ is preferably C₁ -C₆ alkyloxy,more preferably C₁ -C₄ alkyloxy.

At least one hydrogen atom on the alkyloxy may be substituted, andexamples of substituents usable herein include a halogen atom, nitro,amino, C₁ -C₆ alkyl disubstituted (for example, dimethyl-substituted)amino, carboxyl, C₁ -C₆ alkoxy (for example, methoxy), C₁ -C₆alkoxy-substituted C₁ -C₆ alkoxy, a hydroxyl group, sulfoxyl, C₁ -C₆alkylthio (for example, methylthio), mercapto, C₁ -C₆ alkylsulfonyl (forexample, methylsulfonyl), cyano, phenyl, and C₃ -C₁₀ cycloalkyl(preferably C₃ -C₇ cycloalkyl, for example, cyclopropyl), oxiranyl,2-propenyl, and hydroxyiminomethyl.

The C₂ -C₁₀ alkenyloxy represented by R³ is preferably C₂ -C₆alkenyloxy, more preferably C₂ -C₄ alkenyloxy.

At least one hydrogen atom on the alkenyloxy may be substituted, andexamples of substituents usable herein include a halogen atom, nitro,amino, C₁ -C₆ alkyl disubstituted (for example, dimethyl-substituted)amino, carboxyl, C₁ -C₆ alkoxy (for example, methoxy), a hydroxyl group,sulfoxyl, C₁ -C₆ alkylthio (for example, methylthio), mercapto, C₁ -C₆alkylsulfonyl (for example, methylsulfonyl), cyano, phenyl, C₃ -C₁₀cycloalkyl (preferably C₃ -C₇ cycloalkyl, for example, cyclopropyl),oxiranyl, 2-propenyl, and hydroxyiminomethyl.

The C₂ -C₁₀ alkynyloxy represented by R³ is preferably C₂ -C₆alkynyloxy, more preferably C₂ -C₄ alkynyloxy.

At least one hydrogen atom on the alkynyloxy may be substituted, andexamples of substituents usable herein include a halogen atom, nitro,amino, C₁ -C₆ alkyl disubstituted (for example, dimethyl-substituted)amino, carboxyl, C₁ -C₆ alkoxy (for example, methoxy), a hydroxyl group,sulfoxyl, C₁ -C₆ alkylthio (for example, methylthio), mercapto, C₁ -C₆alkylsulfonyl (for example, methylsulfonyl), cyano, phenyl, C₃ -C₁₀cycloalkyl (preferably C₃ -C₇ cycloalkyl, for example, cyclopropyl),oxiranyl, 2-propenyl, and hydroxyiminomethyl.

The C₃ -C₁₀ cycloalkyloxy represented by R³ is preferably C₃ -C₇cycloalkyloxy, and examples thereof include cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

At least one hydrogen atom on the cycloalkyloxy may be substituted, andexamples of substituents usable herein include a halogen atom, nitro,amino, C₁ -C₆ alkyl disubstituted (for example, dimethyl-substituted)amino, carboxyl, C₁ -C₆ alkoxy (for example, methoxy), C₁ -C₆alkoxy-substituted C₁ -C₆ alkoxy, a hydroxyl group, sulfoxyl, C₁ -C₆alkylthio (for example, methylthio), mercapto, C₁ -C₆ alkylsulfonyl (forexample, methylsulfonyl), cyano, phenyl, and C₃ -C₁₀ cycloalkyl(preferably C₃ -C₇ cycloalkyl, for example, cyclopropyl), oxiranyl,2-propenyl, and hydroxyiminomethyl.

Examples of the C₇ -C₁₅ aralkyloxy represented by R³ is preferablybenzyloxy, phenylethoxy, methylbenzyloxy, and naphthylmethoxy.

At least one hydrogen atom on the aralkyloxy may be substituted, andexamples of substituents usable herein include C₁ -C₆ alkyl, a halogenatom, nitro, amino, C₁ -C₆ alkyl disubstituted (for example,dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (for example,methoxy), a hydroxyl group, sulfoxyl, C₁ -C₆ alkylthio (for example,methylthio), mercapto, cyano, phenyl, and C₃ -C₁₀ cycloalkyl (preferablyC₃ -C₇ cycloalkyl, for example, cyclopropyl).

The C₁ -C₁₀ alkylcarbonyloxy represented by R³ is preferably C₁ -C₆alkylcarbonyloxy, more preferably C₁ -C₄ alkylcarbonyloxy.

At least one hydrogen atom on the alkylcarbonyloxy may be substituted,and examples of substituents usable herein include a halogen atom,nitro, amino, C₁ -C₆ alkyl disubstituted (for example,dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (for example,methoxy), a hydroxyl group, sulfoxyl, C₁ -C₆ alkylthio (for example,methylthio), mercapto, C₁ -C₆ alkylsulfonyl (for example,methylsulfonyl), cyano, phenyl, C₃ -C₁₀ cycloalkyl (preferably C₃ -C₇cycloalkyl, for example, cyclopropyl), oxiranyl, 2-propenyl, andhydroxyiminomethyl.

The C₂ -C₁₀ alkenylcarbonyloxy represented by R³ is preferably C₂ -C₆alkenylcarbonyloxy, more preferably C₂ -C₄ alkenylcarbonyloxy.

At least one hydrogen atom on the alkenylcarbonyloxy may be substituted,and examples of substituents usable herein include a halogen atom,nitro, amino, C₁ -C₆ alkyl disubstituted (for example,dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (for example,methoxy), a hydroxyl group, sulfoxyl, C₁ -C₆ alkylthio (for example,methylthio), mercapto, C₁ -C₆ alkylsulfonyl (for example,methylsulfonyl), cyano, phenyl, C₃ -C₁₀ cycloalkyl (preferably C₃ -C₇cycloalkyl, for example, cyclopropyl), oxiranyl, 2-propenyl, andhydroxyiminomethyl.

The C₂ -C₁₀ alkynylcarbonyloxy represented by R³ is preferably C₂ -C₆alkynylcarbonyloxy, more preferably C₂ -C₄ alkynylcarbonyloxy.

At least one hydrogen atom on the alkynylcarbonyloxy may be substituted,and examples of substituents usable herein include a halogen atom,nitro, amino, C₁ -C₆ alkyl disubstituted (for example,dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (for example,methoxy), a hydroxyl group, sulfoxyl, C₁ -C₆ alkylthio (for example,methylthio), mercapto, C₁ -C₆ alkylsulfonyl (for example,methylsulfonyl), cyano, phenyl, C₃ -C₁₀ cycloalkyl (preferably C₃ -C₇cycloalkyl, for example, cyclopropyl), oxiranyl, 2-propenyl, andhydroxyiminomethyl.

The C₃ -C₁₀ cycloalkylcarbonyloxy represented by R³ is preferably C₃-C₁₀ cycloalkylcarbonyloxy, and examples thereof includecyclopropylcarbonyloxy, cyclobutylcarbonyloxy, cyclopentylcarbonyloxy,and cyclohexylcarbonyloxy.

At least one hydrogen atom on the cycloalkylcarbonyloxy may besubstituted, and examples of substituents usable herein include ahalogen atom, nitro, amino, C₁ -C₆ alkyl disubstituted (for example,dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (for example,methoxy), C₁ -C₆ alkoxy-substituted C₁ -C₆ alkoxy, a hydroxyl group,sulfoxyl, C₁ -C₆ alkylthio (for example, methylthio), mercapto, C₁ -C₆alkylsulfonyl (for example, methylsulfonyl), cyano, phenyl, and C₃ -C₁₀cycloalkyl (preferably C₃ -C₇ cycloalkyl, for example, cyclopropyl),oxiranyl, 2-propenyl, and hydroxyiminomethyl.

Examples of the C₇ -C₁₅ aromatic acyloxy represented by R³ includebenzoyloxy, toluoyloxy, and naphthoyloxy.

At least one hydrogen atom on the aromatic acyloxy may be substituted,and examples of substituents usable herein include C₁ -C₆ alkyl, ahalogen atom, nitro, amino, C₁ -C₆ alkyl disubstituted (for example,dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (for example,methoxy), a hydroxyl group, sulfoxyl, C₁ -C₆ alkylthio (for example,methylthio), mercapto, C₁ -C₆ alkylsulfonyl (for example,methylsulfonyl), cyano, phenyl, and C₃ -C₁₀ cycloalkyl (preferably C₃-C₇ cycloalkyl, for example, cyclopropyl), oxiranyl, 2-propenyl, andhydroxyiminomethyl.

Examples of the C₇ -C₁₅ aralkylcarbonyloxy represented by R³ includebenzylcarbonyloxy, phenylethylcarbonyloxy, methylbenzylcarbonyloxy, andnaphthylmethylcarbonyloxy.

At least one hydrogen atom on the aralkylcarbonyloxy may be substituted,and examples of substituents usable herein include C₁ -C₆ alkyl, ahalogen atom, nitro, amino, C₁ -C₆ alkyl disubstituted (for example,dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (for example,methoxy), a hydroxyl group, sulfoxyl, C₁ -C₆ alkylthio (for example,methylthio), mercapto, cyano, phenyl, and C₃ -C₁₀ cycloalkyl (preferablyC₃ -C₇ cycloalkyl, for example, cyclopropyl).

The C₁ -C₁₀ alkylthio represented by R³ is preferably C₁ -C₆ alkylthio,more preferably C₁ -C₄ alkylthio.

At least one hydrogen atom on the alkylthio may be substituted, andexamples of substituents usable herein include a halogen atom, nitro,amino, C₁ -C₆ alkyl disubstituted (for example, dimethyl-substituted)amino, carboxyl, C₁ -C₆ alkoxy (for example, methoxy), C₁ -C₆alkoxy-substituted C₁ -C₆ alkoxy, a hydroxyl group, sulfoxyl, C₁ -C₆alkylthio (for example, methylthio), mercapto, C₁ -C₆ alkylsulfonyl (forexample, methylsulfonyl), cyano, phenyl, and C₃ -C₁₀ cycloalkyl(preferably C₃ -C₇ cycloalkyl, for example, cyclopropyl), oxiranyl,2-propenyl, and hydroxyiminomethyl.

The C₂ -C₁₀ alkenylthio represented by R³ is preferably C₂ -C₆alkenylthio, more preferably C₂ -C₄ alkenylthio.

At least one hydrogen atom on the alkenylthio may be substituted, andexamples of substituents usable herein include a halogen atom, nitro,amino, C₁ -C₆ alkyl disubstituted (for example, dimethyl-substituted)amino, carboxyl, C₁ -C₆ alkoxy (for example, methoxy), a hydroxyl group,sulfoxyl, C₁ -C₆ alkylthio (for example, methylthio), mercapto, C₁ -C₆alkylsulfonyl (for example, methylsulfonyl), cyano, phenyl, C₃ -C₁₀cycloalkyl (preferably C₃ -C₇ cycloalkyl, for example, cyclopropyl),oxiranyl, 2-propenyl, and hydroxyiminomethyl.

The C₂ -C₁₀ alkynylthio represented by R³ is preferably C₂ -C₆alkynylthio, more preferably C₂ -C₄ alkynylthio.

At least one hydrogen atom on the alkynylthio may be substituted, andexamples of substituents usable herein include a halogen atom, nitro,amino, C₁ -C₆ alkyl disubstituted (for example, dimethyl-substituted)amino, carboxyl, C₁ -C₆ alkoxy (for example, methoxy), a hydroxyl group,sulfoxyl, C₁ -C₆ alkylthio (for example, methylthio), mercapto, C₁ -C₆alkylsulfonyl (for example, methylsulfonyl), cyano, phenyl, C₃ -C₁₀cycloalkyl (preferably C₃ -C₇ cycloalkyl, for example, cyclopropyl),oxiranyl, 2-propenyl, and hydroxyiminomethyl.

The C₃ -C₁₀ cycloalkylthio represented by R³ is preferably C₃ -C₇cycloalkylthio, and examples thereof include cyclopropylthio,cyclobutylthio, cyclopentylthio, and cyclohexylthio.

At least one hydrogen atom on the cycloalkylthio may be substituted, andexamples of substituents usable herein include a halogen atom, nitro,amino, C₁ -C₆ alkyl disubstituted (for example, dimethyl-substituted)amino, carboxyl, C₁ -C₆ alkoxy (for example, methoxy), C₁ -C₆alkoxy-substituted C₁ -C₆ alkoxy, a hydroxyl group, sulfoxyl, C₁ -C₆alkylthio (for example, methylthio), mercapto, C₁ -C₆ alkylsulfonyl (forexample, methylsulfonyl), cyano, phenyl, and C₃ -C₁₀ cycloalkyl(preferably C₃ -C₇ cycloalkyl, for example, cyclopropyl), oxiranyl,2-propenyl, and hydroxyiminomethyl.

Examples of the C₆ -C₁₅ arylthio represented by R³ include phenylthio,toluylthio, and naphthylthio.

At least one hydrogen atom on the arylthio may be substituted, andexamples of substituents usable herein include C₁ -C₆ alkyl, a halogenatom, nitro, amino, C₁ -C₆ alkyl disubstituted (for example,dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (for example,methoxy), a hydroxyl group, sulfoxyl, C₁ -C₆ alkylthio (for example,methylthio), mercapto, C₁ -C₆ alkylsulfonyl (for example,methylsulfonyl), cyano, phenyl, and C₃ -C₁₀ cycloalkyl (preferably C₃-C₇ cycloalkyl, for example, cyclopropyl), oxiranyl, 2-propenyl, andhydroxyiminomethyl.

Examples of the C₇ -C₁₅ aralkylthio represented by R³ includebenzylthio, phenylethylthio, methylbenzylthio, and naphthylthio.

At least one hydrogen atom on the aralkylthio may be substituted, andsubstituents usable herein include, for example, C₁ -C₆ alkyl, a halogenatom, nitro, amino, C₁ -C₆ alkyl disubstituted (for example,dimethyl-substituted) amino, carboxyl, C₁ -C₆ alkoxy (for example,methoxy), a hydroxyl group, sulfoxyl, C₁ -C₆ alkylthio (for example,methylthio), mercapto, cyano, phenyl, and C₃ -C₁₀ cycloalkyl (preferablyC₃ -C₇ cycloalkyl, for example, cyclopropyl).

Among the compounds represented by the formula (I) according to thepresent invention, a group of preferred compounds include thoserepresented by the formula (I) wherein

R¹ represents

optionally substituted C₁ -C₁₀ alkyl or

optionally substituted C₇ -C₁₅ aralkyl;

R² represents

a hydrogen atom,

optionally substituted C₁ -C₁₀ alkylcarbonyl,

optionally substituted C₃ -C₁₀ cycloalkylcarbonyl,

optionally substituted C₇ -C₁₅ aromatic acyl,

optionally substituted C₂ -C₁₅ heteroaromatic acyl having at least onehetero atom selected from the group consisting of nitrogen, oxygen, andsulfur atoms,

optionally substituted C₃ -C₁₅ saturated heterocyclic acyl having atleast one hetero atom selected from the group consisting of nitrogen,oxygen, and sulfur atoms,

optionally substituted C₁ -C₁₀ alkyl,

optionally substituted C₂ -C₁₀ alkenyl,

optionally substituted C₇ -C₁₅ aralkyl,

carbamoyl,

optionally substituted N-C₁ -C₁₀ alkylcarbamoyl,

optionally substituted N-C₆ -C₁₅ aromatic carbamoyl,

optionally substituted N-C₇ -C₁₅ aralkylcarbamoyl,

optionally substituted N,N-di-C₁ -C₁₀ alkylaminocarbonyl,

optionally substituted N-C₃ -C₁₀ cycloalkylcarbamoyl,

optionally substituted C₁ -C₁₀ alkoxycarbonyl,

optionally substituted C₆ -C₁₅ aryloxycarbonyl,

optionally substituted C₁ -C₁₅ heteroaromatic thiocarbonyl having atleast one hetero atom selected from the group consisting of nitrogen,oxygen, and sulfur atoms,

optionally substituted C₂ -C₁₅ saturated heterocyclic thiocarbonylhaving at least one hetero atom selected from the group consisting ofnitrogen, oxygen, and sulfur atoms, or

optionally substituted N-C₁ -C₁₀ alkyl-thiocarbamoyl; and

R³ represents

a hydrogen atom,

a hydroxyl group,

optionally substituted C₁ -C₁₀ alkyloxy,

optionally substituted C₁ -C₁₀ alkylcarbonyloxy,

optionally substituted C₁ -C₁₀ alkylthio, or

optionally substituted C₆ -C₁₅ arylthio.

Among the above group of preferred compounds, a group of more preferredcompounds include those represented by the formula (I) wherein

R¹ represents

C₁ -C₁₀ alkyl or

C₇ -C₁₅ aralkyl optionally substituted by C₁ -C₆ alkoxy;

R² represents

a hydrogen atom,

C₁ -C₁₀ alkylcarbonyl,

C₃ -C₁₅ cycloalkylcarbonyl,

C₆ -C₁₅ aromatic acyl optionally substituted by C₁ -C₆ alkoxy or nitro,

C₂ -C₁₅ heteroaromatic acyl having at least one hetero atom selectedfrom the group consisting of nitrogen, oxygen, and sulfur atoms,

C₃ -C₁₅ saturated heterocyclic acyl, having at least one hetero atomselected from the group consisting of nitrogen, oxygen, and sulfuratoms, optionally substituted by C₁ -C₆ alkyl or C₁ -C₆ alkoxy-C₁ -C₆alkyl,

C₁ -C₁₀ alkyl optionally substituted by C₃ -C₇ cycloalkyl or hydroxyl,

C₂ -C₁₀ alkenyl optionally substituted by phenyl,

C₇ -C₁₅ aralkyl optionally substituted by C₁ -C₆ alkoxy, carbamoyl,

N-C₁ -C₁₀ alkylcarbamoyl in which hydrogen atom(s) on the alkyl isoptionally substituted by a hydroxyl group,

N-C₆ -C₁₅ aromatic carbamoyl,

N-C₇ -C₁₅ aralkylcarbamoyl,

N,N-di-C₁ -C₁₀ alkylaminocarbonyl,

N-C₃ -C₁₀ cycloalkylcarbamoyl,

C₁ -C₁₀ alkoxycarbonyl,

C₆ -C₁₅ aryloxycarbonyl,

C₁ -C₁₅ heteroaromatic thiocarbonyl having at least one nitrogen atom,

C₂ -C₁₅ saturated heterocyclic thiocarbonyl having at least one nitrogenatom, or

N-C₁ -C₁₀ alkyl-thiocarbamoyl; and

R³ represents

a hydrogen atom,

a hydroxyl group,

C₁ -C₁₀ alkyloxy optionally substituted by C₃ -C₁₀ cycloalkyl,

C₁ -C₁₀ alkylcarbonyloxy,

C₁ -C₁₀ alkylthio, or

C₆ -C₁₅ arylthio.

Another group of preferred compounds include those represented by theformula (I) wherein

R¹ represents

C₁ -C₆ alkyl or

benzyl optionally substitute by C₁ -C₆ alkoxy;

R² represents

a hydrogen atom,

C₁ -C₆ alkylcarbonyl,

C₃ -C₇ cycloalkylcarbonyl,

benzoyl optionally substituted by C₁ -C₆ alkoxy or nitro,

five- or six-membered heteroaromatic acyl having one or two nitrogen,oxygen, or sulfur atoms,

five- or six-membered heteroaromatic acyl having nitrogen and sulfuratoms,

five- or six-membered saturated heterocyclic acyl having a oxygen orsulfur atom,

C₁ -C₆ alkyl optionally substituted by C₃ -C₇ cycloalkyl or hydroxy,

C₂ -C₆ alkenyl optionally substituted by phenyl,

benzyl optionally substituted by C₁ -C₆ alkoxy, carbamoyl,

N-C₁ -C₆ alkylcarbamoyl in which hydrogen atom(s) on the alkyl isoptionally substituted by a hydroxyl group,

N-phenylcarbamoyl,

N-benzylcarbamoyl,

N,N-di-C₁ -C₆ alkylaminocarbonyl,

N-C₃ -C₇ cycloalkylcarbamoyl,

C₁ -C₆ alkoxycarbonyl,

phenyloxycarbonyl,

pyrimidylthiocarbonyl,

pyrrolidylthiocarbonyl, or

N-C₁ -C₆ alkyl-thiocarbamoyl; and

R³ represents

a hydrogen atom,

a hydroxyl group,

C₁ -C₆ alkyloxy optionally substituted by C₃ -C₇ cycloalkyl,

C₁ -C₆ alkylcarbonyloxy,

C₁ -C₆ alkylthio, or

phenylthio.

Since the compounds represented by the formula (I) according to thepresent invention have several asymmetric carbons, various isomersattributable to these carbons are considered. The present inventionembraces these individual isomers and mixtures thereof.

The compounds represented by the formula (I) may be present in the formof a salt. Examples of the salt include pharmacologically acceptablesalts, and specific examples thereof include lithium, sodium, potassium,magnesium, and calcium salts; salts with ammonium and suitable non-toxicamines, for example, C₁ -C₆ alkylamine (for example, triethylamine)salts, C₁ -C₆ alkanolamine (for example, diethanolamine ortriethanolamine) salts, procaine salts, cyclohexylamine (for example,dicyclohexylamine) salts, benzylamine (for example, N-methylbenzylamine,N-ethylbenzylamine, N-benzyl-β-phenethylamine,N,N-dibenzylethylenediamine, or dibenzylamine) salts, and heterocyclicamines (for example, morpholine or N-ethylpyridine) salts; salts ofhydrohalogenic acids such as hydrofluoric acid, hydrochloric acid,hydrobromic acid and hydroiodic acid; inorganic acid salts such assulfate, nitrate, phosphate, perchlorate and carbonate; salts ofcarboxylic acids such as acetic acid, trichloroacetic acid,trifluoroacetic acid, hydroxyacetic acid, lactic acid, citric acid,tartaric acid, oxalic acid, benzoic acid, mandelic acid, butyric acid,maleic acid, propionic acid, formic acid and malic acid; salts of aminoacids such as arginic acid, aspartic acid and glutamic acid; and saltsof organic acids such as methanesulfonic acid and p-toluenesulfonicacid.

Use of Compounds Represented by Formula (I)/Pharmaceutical Compositions

The compounds, represented by the formula (I), according to the presentinvention have progesterone receptor binding inhibitory activity and,hence, can be used as therapeutic and prophylactic agents forprogesterone-related diseases. The progesterone receptor has beenreported to be expressed in breast, uterus, ovary, bone, and centralnerve. Therefore, the compounds represented by the formula (I) areuseful as therapeutic and prophylactic agents for progesterone-relateddiseases in these organs. More specifically, they are useful ascarcinostatic agents for breast cancer and ovarian cancer, therapeuticagents for hysteromyoma, endometriosis, meningioma, and myeloma,abortifacients, oral contraceptive pills, and therapeutic andprophylactic agents for osteoporosis and climacteric disturbance. Inparticular, the compounds represented by the formula (I) according tothe present invention have no steroid skeleton and, hence, areconsidered to be advantageously free from side effect inherent insteroid such as found in conventional progesterone receptor bindinginhibitors having a steroid skeleton.

A pharmaceutical composition comprising as an active ingredient acompound of the present invention can be administered either orally orparenterally (e.g., intravenous injection, intramuscular injection,subcutaneous administration, rectal administration, percutaneousadministration) to humans or animals other than humans.

The pharmaceutical composition comprising as an active ingredient acompound of the present invention may be made into a preparationsuitable for an administration route to be adopted. Specifically, it maybe made into any of the following preparations: an injection forintravenous or intramuscular injection; a capsule, a tablet, a granule,a powder, a pill, fine subtilaes, or a troche for oral administration; apreparation for rectal administration; an oleaginous suppository; and anaqueous suppository. The above-described various preparations can beprepared by a conventional method using an excipient, a filler, abinder, a wetting agent, a disintegrating agent, a surface active agent,a lubricant, a dispersing agent, a buffer, a preservative, asolubilizer, an antiseptic, a flavor, a soothing agent, a stabilizer andthe like. Examples of the above additives which are nontoxic andemployable in the preparations include lactose, fructose, glucose,starch, gelatin, magnesium carbonate, synthetic magnesium silicate,talc, magnesium stearate, methyl cellulose, carboxymethyl cellulose or asalt thereof, gum arabic, polyethylene glycol, syrup, vaseline,glycerin, ethanol, propylene glycol, citric acid, sodium chloride,sodium sulfite and sodium phosphate.

The dosage of the compound of the present invention is properlydetermined in consideration of the symptom and the age and sex of apatient for each case. When the compound is intravenously administeredas the above therapeutic or prophylactic agent, especiallycontraceptive, or therapeutic agent for breast cancer or ovarian cancer,approximately 0.01 to 1000 mg, preferably 0.1 to 100 mg, of the compoundis generally administered per day for adult human, at one time orseveral times. On the other hand, for intramuscular administration,approximately 0.01 to 1000 mg, preferably 0.1 to 100 mg, of the compoundis generally administered per day for adult human, at one time orseveral times. For oral administration, approximately 0.5 to 2000 mg,preferably 1 to 1000 mg, of the compound is generally administered perday for adult human, at one time or several times.

Preparation of Compounds Represented by Formula (I)

The compounds represented by the formula (I) according to the presentinvention can be prepared from substance PF1092C as a starting compoundthrough the following processes. The substance PF1092C can be prepared,for example, by Steps (A) to (D) described in Japanese Patent Laid-OpenNo. 253467/1996 or EP722940A.

Process (A) ##STR4## wherein R¹ and R² are as defined above in theformula (I);

R⁴ represents an optionally substituted C₁ -C₁₀ alkyl, optionallysubstituted C₂ -C₁₀ alkenyl, optionally substituted C₂ -C₁₀ alkynyl,optionally substituted C₃ -C₁₀ cycloalkyl, optionally substituted C₆-C₁₅ aryl, or optionally substituted C₇ -C₁₅ aralkyl; and

R⁵ represents a hydrogen atom, an optionally substituted C₁ -C₁₀ alkyl,optionally substituted C₂ -C₁₀ alkenyl, optionally substituted C₂ -C₁₀alkynyl, optionally substituted C₃ -C₁₀ cycloalkyl, or optionallysubstituted C₇ -C₁₅ aralkyl.

In the process (A), the starting compound PF1092C represented by theformula (III) is reacted with a sulfonyl halide in the presence of anecessary or excess amount of a base. The reaction product is thenimmediately subjected to a coupling reaction with a primary aminerepresented by R¹ --NH₂ (wherein R¹ is as defined above in the formula(I)) to give an amide compound represented by the formula (IV).

Bases usable in the sulfonylation include organic bases such aspyridine, lutidine, collidine, triethylamine, and dimethylaminopyridine.Preferably, diisopropylethylamine is used in an amount of one to threeequivalents. Sulfonyl halides usable herein include p-toluenesulfonylchloride and benzylsulfonyl chloride. Preferably, methanesulfonylchloride is used in an amount of one to two equivalents.

The reaction proceeds in a good yield in a suitable solvent (forexample, methylene chloride, chloroform, benzene, toluene, or xylene) ata temperature in the range of -30° C. to 10° C., and the reaction timeis about 5 min to one hr.

Primary amines usable in the subsequent amidation include primaryalkylamines having an organic group corresponding to R¹, such asmethylamine, ethylamine, isopropylamine, benzylamine, and4-methoxybenzylamine, and preferably, the primary amine is used in anamount of one to 10 equivalents.

The reaction proceeds in a good yield in a suitable solvent (forexample, methylene chloride, chloroform, 1,4-dioxane, ether, ortetrahydrofuran (THF), preferably THF) at a temperature in the range of0 to 50° C., and the reaction time is about 1 to 24 hr.

In the process (A), the compound represented by the formula (IV) is thensubjected to a ring-closing reaction with a carboxylic acid to give acompound represented by the formula (V) with a carbonyloxy group havingα configuration being stereoselectively introduced thereinto. In thering-closing reaction, an aliphatic carboxylic acid or an aromaticcarboxylic acid R⁴ --COOH having an organic group corresponding todesired R⁴ --CO-- (wherein R⁴ is as defined above) of the compoundrepresented by the formula (V), such as acetic acid, propionic acid, orbutyric acid is used in an amount of preferably five (5) equivalents toan excess amount. Therefore, the selection of the carboxylic acid inthis step is important. The reaction proceeds in a solvent (for example,THF, 1,4-dioxane, or acetonitrile, preferably acetonitrile) at atemperature in the range of 0 to 100° C., and the reaction time is about1 to 24 hr.

The step of introducing R² into the compound represented by the formula(V) to give the compound represented by the formula (VI) may be carriedout by methods (1) to (5), described below, depending upon the type ofthe group R².

On the other hand, in the process (A), a compound represented by theformula (VII) with the substituent R⁵ O-held at the α configuration isderived from the compound represented by the formula (V) by asubstitution reaction with a nucleophilic reagent. The nucleophilicreagent is determined by the side chain of R⁵ O introduced into thecompound represented by the formula (VII). Therefore, R⁵ --OH (whereinR⁵ is as defined above) is used as the nucleophilic agent, and specificexamples of compounds usable herein include optionally substituted C₁-C₁₀ alkyl alcohols, optionally substituted C₂ -C₁₀ alkenyl alcohols,optionally substituted C₂ -C₁₀ alkynyl alcohols, optionally substitutedC₃ -C₁₀ cycloalkyl alcohols, and optionally substituted C₇ -C₁₅ aralkylalcohols. Further, for example, when R⁵ represents a C₁ -C₁₀ alkyl sidechain, methanol, ethanol, propanol, isopropanol, or butanol is used asthe nucleophilic reagent. This nucleophilic reagent can serve also asthe solvent for the reaction and hence is preferably used in largeexcess. The reaction proceeds in a good yield at a temperature in therange of 20 to 100° C., and the reaction time is about 30 min to 24 hr.

When the R⁵ in the compound represented by the formula (VII) representsa hydrogen atom, water may be used as the nucleophilic reagent. WhenTHF, 1,4-dioxane, or acetonitrile, preferably acetonitrile, is used asthe solvent, the reaction smoothly proceeds. Preferably, water is usedin large excess. The reaction proceeds in a good yield at a temperaturein the range of 20 to 100° C., and the reaction time is about 30 min to24 hr.

The step of introducing R² into the compound represented by the formula(VII) to give the compound represented by the formula (VIII) may becarried out by methods (1) to (5), described below, depending upon thetype of the group R².

Process (B)

The compounds represented by the formula (I) according to the presentinvention may be synthesized also by the following process. ##STR5##wherein R¹ is as defined above in the formula (I); and

R⁶ represents an optionally substituted C₁ -C₁₀ alkyl, optionallysubstituted C₂ -C₁₀ alkenyl, optionally substituted C₂ -C₁₀ alkynyl,optionally substituted C₃ -C₁₀ cycloalkyl, optionally substituted C₆-C₁₅ aryl, or optionally substituted C₇ -C₁₅ aralkyl.

In the process (B), the compound represented by the formula (V) or (VII)is reacted with a thiol compound represented by the formula R⁶ -SH(wherein R⁶ is as defined above) in the presence of a necessary amountof an organic acid to give a compound represented by the formula (IX).In this reaction, preferably, the compound R⁶ -SH is used in an amountof one equivalent to an excess amount. Organic acids usable in thereaction include camphorsulfonic acid, p-toluenesulfonic acid, andmethanesulfonic acid. Preferably, methanesulfonic acid is used in anamount of 0.1 to 1 equivalent. The reaction proceeds in a suitablesolvent (for example, chloroform, benzene, toluene, xylene, or methylenechloride with methylene chloride being preferred) at a temperature inthe range of 0 to 100° C., and the reaction time is about one min to onehr.

The step of introducing the group R² into the compound represented bythe formula (IX) to give the compound represented by the formula (X) maybe carried out by methods (1) to (5), described below, depending uponthe type of the group R².

Process (C) ##STR6## wherein R¹, R⁴, and R⁵ are as defined above.

In the process (C), the compound represented by the formula (V) or (VII)may be reacted with a necessary amount of an organic acid to give acompound represented by the formula (II). In this reaction, organicacids usable herein include camphorsulfonic acid, p-toluenesulfonicacid, and methanesulfonic acid. Preferably, methanesulfonic acid is usedin an amount of 0.1 to 1 equivalent. The reaction proceeds in a goodyield in a suitable solvent (for example, methylene chloride,chloroform, benzene, toluene, or xylene) at a temperature in the rangeof 20 to 10° C., and the reaction time is about one min to one hr.

Subsequently, the compound represented by the formula (II) may bereduced with sodium borohydride to give a compound represented by theformula (XI) with the 6-position being stereoselectively converted to ahydroxyl group of β configuration. Reducing agents usable in thisreduction reaction include lithium borohydride, tetrabutyl ammoniumborohydride, and sodium borohydride. Preferably, sodium borohydride isused in an amount of one to five equivalents. The reaction proceeds in agood yield in a solvent (for example, an alcoholic solvent, preferablymethanol) at a temperature in the range of -10° C. to 50° C., and thereaction time is about one min to 3 hr.

The step of introducing the group R² into the compound represented bythe formula (XI) to give the compound represented by the formula (XII)may be carried out by methods (1) to (5), described below, dependingupon the type of the group R².

Process (D)

The compounds represented by the formula (I) according to the presentinvention may be synthesized also by the following process. ##STR7##wherein R¹ is as defined above in the formula (I);

R² is as defined above in the formula (I) excluding the hydrogen atom;and

R⁵ is as defined above.

In this process, only the 7-position in the compound represented by theformula (VIII) is directly converted to a desired organic group(excluding a hydrogen atom) to give the compound represented by theformula (I) (wherein R¹ is defined above in the formula (I), R² is asdefined above in the formula (I) excluding the hydrogen, atom, and R³ isas defined above in the formula (I) excluding the hydrogen atom).

In particular, the starting compound represented by the formula (VIII)is subjected to a substitution reaction with a compound having anorganic group corresponding to desired R³ optionally in the presence ofan acid in a necessary amount or an excess amount to give the compoundrepresented by the formula (I). Examples of compounds having an organicgroup corresponding to R³ include alcohols, thiols, carboxylic acids,and water. Preferably, the substitution reaction using an alkyl alcohol,an alkyl thiol, an aryl thiol or the like is carried out in the presenceof an organic acid, such as camphorsulfonic acid, p-toluenesulfonicacid, or methanesulfonic acid. Preferably, methanesulfonic acid is usedin an amount of 0.1 to 1 equivalent. On the other hand, when analiphatic carboxylic acid or an aromatic carboxylic acid is used, thereis no need to add any acid because the reagent per se acts as an acidcatalyst. In the case of the substitution reaction using water, use ofhydrochloric acid as the acid catalyst in excess is preferred. Thereaction proceeds in a solvent (for example, methylene chloride,chloroform, benzene, toluene, xylene, or acetonitrile) at a temperaturein the range of from 0 to 100° C., and the reaction time is about onemin to one hr.

Introduction of R²

The modification of a hydroxyl group at the 6-position, that is, theintroduction of the modification group corresponding to R², of thecompound represented by the formula (I) (wherein R¹ is as defined above,R² represents a hydrogen atom, and R³ is as defined above in the formula(I) excluding the hydroxyl group) may be preferably carried out by anyone of the following methods (1) to (5).

Method (1)

The compounds represented by the formula (I) [wherein

R¹ is as defined above in the formula (I);

R² represents optionally substituted C₁ -C₁₀ alkylcarbonyl, optionallysubstituted C₂ -C₁₀ alkenylcarbonyl, optionally substituted C₂ -C₁₀alkynylcarbonyl, optionally substituted C₃ -C₁₅ cycloalkylcarbonyl,optionally substituted C₇ -C₁₅ aromatic acyl, optionally substituted C₇-C₁₅ aralkylcarbonyl, optionally substituted C₂ -C₁₅ heteroaromatic acylhaving at least one nitrogen, oxygen, and sulfur atom, or optionallysubstituted C₃ -C₁₅ saturated heterocyclic acyl having at least onenitrogen, oxygen, or sulfur atom; and

R³ is as defined above in the formula (I) excluding the hydroxyl group]may be prepared by reacting the compound represented by the formula (I)(wherein R¹ is as defined above in the formula (I), R² represents ahydrogen atom, and R is as defined above in the formula (I) excludingthe hydroxyl group) with a suitable acylating agent in the presence of abase.

The acylating agent may be properly selected according to the structureof desired R², and examples thereof include optionally substituted C₁-C₁₀ alkylcarbonyl halides (for example, acetyl chloride), optionallysubstituted C₂ -C₁₀ alkenylcarbonyl halides, optionally substituted C₂-C₁₀ alkynylcarbonyl halides, C₃ -C₁₅ cycloalkylcarbonyl halides,optionally substituted C₇ -C₁₅ aralkylcarbonyl halides, optionallysubstituted C₆ -C₁₅ aromatic acyl halides, optionally substituted C₂-C₁₅ heteroaromatic acyl halides having at least one nitrogen, oxygen,or sulfur atom, and acid anhydrides, such as acetic anhydride andpropionic anhydride. Preferably, the acylating agent is used in anamount of 1 to 5 equivalents. The reaction may be carried out in asolvent, such as pyridine, which serves also as a base, or in acombination of an aprotic solvent, used in the conventional acylation,with an organic base. The reaction proceeds in a good yield at atemperature in the range of 20 to 60° C., and the reaction time is about1 to 24 hr.

The production process of the compound wherein R² representsimidazol-1-ylcarbonyl among optionally substituted C₂ -C₁₅heteroaromatic acyls having at least one nitrogen, oxygen, or sulfuratom will be described in the method (3) below.

Method (2)

The compounds represented by the formula (I) [wherein

R¹ is as defined above in the formula (I);

R² represents optionally substituted C₁ -C₁₀ alkyl, optionallysubstituted C₂ -C₁₀ alkenyl, optionally substituted C₂ -C₁₀ alkynyl,optionally substituted C₃ -C₁₀ cycloalkyl, or optionally substituted C₇-C₁₅ aralkyl;

R³ represents optionally substituted C₁ -C₁₀ alkyloxy, optionallysubstituted C₂ -C₁₀ alkenyloxy, optionally substituted C₂ -C₁₀alkynyloxy, optionally substituted C₃ -C₁₀ cycloalkyloxy, or optionallysubstituted C₇ C₁₅ aralkyloxy] may be prepared by reacting the compoundrepresented by the formula(I) (wherein R¹ is as defined in claim 1, R²represents a hydrogen atom, and R³ represents optionally substituted C₁-C₁₀ alkyloxy, optionally substituted C₂ -C₁₀ alkenyloxy, optionallysubstituted C₂ -C₁₀ alkynyloxy, optionally substituted C₃ -C₁₀cycloalkyloxy, or optionally substituted C₇ -C₁₅ aralkyloxy) with asuitable alkylating agent in the presence of a base.

The alkylating agent may be properly selected according to the structureof desired R², and examples thereof include optionally substituted C₁-C₁₀ alkyl halides (for example, methyl iodide), optionally substitutedC₂ -C₁₀ alkenyl halides, optionally substituted C₂ -C₁₀ alkynyl halides,optionally substituted C₃ -C₁₀ cycloalkyl halides, and optionallysubstituted C₇ -C₁₅ aralkyl halides. Preferably, the alkylating agent isused in an amount of one equivalent to an excess amount. Bases usable inthe alkylation include metal hydrides, such as sodium hydride andpotassium hydride. Preferably, the base is used in an amount of 1 to 20equivalents. The reaction proceeds in a good yield in a suitable solvent(for example, a solvent used in the conventional alkylation, such asdimethylformamide (DMF), benzene, toluene, methylene chloride, orchloroform) at a temperature in the range of 20 to 100° C., the reactiontime is about 30 min to 24 hr.

Method (3)

The compounds represented by the formula (I) [wherein

R¹ is as defined above in the formula (I);

R² represents carbamoyl, optionally substituted C₁ -C₁₀ alkylcarbamoyl,N, N-di-C₁ -C₁₀ alkylaminocarbonyl, optionally substituted C₃ -C₁₀cycloalkylcarbamoyl, optionally substituted C₆ -C₁₅ aromatic carbamoyl,or optionally substituted C₇ -C₁₅ aralkylcarbamoyl; and

R³ is as defined above in the formula (I) excluding the hydroxyl group]may be prepared as follows.

The compound represented by the formula (I) (wherein R¹ is as definedabove in the formula (I), R² represents a hydrogen atom, and R³ is asdefined above in the formula (I) excluding the hydroxyl group) isreacted with 1,1-carbonyldiimidazole to give a compound with the6-position being imidazol-1-ylcarbonylated. Preferably,1,1-carbonyldiimidazole is used in an amount of 1 to 3 equivalents. Thereaction proceeds in a good yield in a suitable solvent (for example,methylene chloride, chloroform, benzene, toluene, or xylene) at atemperature in the range of -30° C. to 30° C., and the reaction time isabout 30 min to 24 hr.

The compound thus prepared is optionally reacted with an equivalent of amethylating agent to give an onium ion which is then reacted withammonia or an amine, such as C₁ -C₁₀ alkylamine optionally having aprimary or secondary substituent (for example, n-propylamine), N,N-di-C₁-C₁₀ alkylamine, optionally substituted C₃ -C₁₀ cycloalkylamine,optionally substituted C₇ -C₁₅ aralkylamine, optionally substituted C₆-C₁₅ aromatic amine, or optionally substituted C₂ -C₁₅ saturatedheterocyclic amine having at least one nitrogen, oxygen, or sulfur atomto give a compound with R² being carbamoylated.

The methylation which is first carried out is effective in thesubstitution reaction with an amine having poor reactivity. Use of aboutone equivalent of an alkylating agent having a high onium ionizationcapability, such as methyl triflate, is preferred. The reaction proceedsin a good yield in a solvent (for example, methylene chloride,chloroform, ether, or THF) at a temperature in the range of -20° C. to30° C., and the reaction time is about 10 min to one hr.

The amount of the reagent used in the subsequent reaction with the amineis preferably one equivalent to an excess amount. The reaction proceedsin a good yield in a solvent (for example, toluene, benzene, xylene, orDMF) at a temperature in the range of 0 to 100 ° C., and the reactiontime is about 30 min to 3 days.

Further, the compound represented by the formula(I) (wherein R¹ is asdefined above in the formula (I), R² represents a hydrogen atom, and R³is as defined above in the formula (I) excluding the hydroxyl group) maybe used as a starting compound and reacted with a reagent capable ofcarbamoylating the hydroxyl group in the presence of a necessary amountof a base to give a compound with R² being carbamoylated.

Bases usable in the carbamoylation include organic bases, such aspyridine, lutidine, collidine, triethylamine, and diisopropylethylamine.Preferably, 4-dimethylaminopyridine is used in a catalytic amount. Anisocyanate, such as propyl isocyanate, is used as a carbamoylatingreagent in an amount of preferably one equivalent to an excess amount.The reaction proceeds in a good yield in a solvent (for example, DMF,methylene chloride, chloroform, benzene, or toluene with DMF beingpreferred) at a temperature in the range of 25 to 120 ° C., and thereaction time is about 1 to 24 hr.

Method (4)

The compounds represented by the formula (I) [wherein

R¹ is as defined above in the formula (I);

R² represents optionally substituted C₁ -C₁₀ alkoxycarbonyl, optionallysubstituted C₆ -C₁₅ aryloxycarbonyl, optionally substituted C₇ -C₁₅aralkyloxycarbonyl; and

R³ is as defined above in the formula (I) excluding the hydroxyl group]may be prepared by carbonating the compound represented by the formula(I) (wherein R¹ is as defined above in the formula (I), R² represents ahydrogen atom, and R³ represents is as defined above in the formula (I)excluding the hydroxyl group).

Examples of carbonating reagents usable herein include optionallysubstituted C₁ -C₁₀ alkoxycarbonyl halides (for example, ethoxycarbonylchloride), optionally substituted C₆ -C₁₅ aryloxycarbonyl halides, andoptionally substituted C₇ -C₁₅ aralkyloxycarbonyl halides. Preferably,the reagent is used in an amount of 1 to 5 equivalents. The reactionproceeds in a good yield in a solvent (pyridine serving also as a base,or a combination of an aprotic solvent and an organic base used in theconventional carbonation) at a temperature in the range of 20 to 60° C.,and the reaction time is about 1 to 30 hr.

Method (5)

The compounds represented by the formula (I) [wherein

R¹ is as defined above in the formula (I);

R² represents optionally substituted C₁ -C₁₅ heteroaromatic thiocarbonylgroup having at least one nitrogen, oxygen, or sulfur atom, optionallysubstituted C₂ -C₁₅ saturated heterocyclic thiocarbonyl having at leastone nitrogen, oxygen, or sulfur atom, or optionally substituted C₁ -C₁₀alkylthiocarbamoyl; and

R³ is as defined above in the formula (I) excluding the hydroxyl group]may be prepared as follows.

The compound represented by the formula (I) (wherein R¹ is as definedabove in the formula (I), R² represents a hydrogen atom, and R³ is asdefined above in the formula (I) excluding the hydroxyl group) isreacted with 1,1'-thiocarbonyldiimidazole to prepare a compound with R²being imidazol-1-ylthiocarbonylated. In this reaction, preferably,1,1'-thiocarbonyldiimidazole is used in an amount of 1 to 3 equivalents.The reaction proceeds in a good yield in a solvent (for example,methylene chloride, chloroform, benzene, toluene, or xylene) at atemperature in the range of 0 to 60° C., and the reaction time is aboutone hr to two days.

The compound thus prepared is then reacted with an amine, such as C₁-C₁₀ alkylamine optionally having a primary or secondary substituent, C₃-C₁₀ cycloalkylamine, optionally substituted C₇ -C₁₅ aralkylamine,optionally substituted C₆ -C₁₅ aromatic amine, or optionally substitutedC₂ -C₁₅ saturated heterocyclic amine having at least one nitrogen,oxygen, or sulfur atom to give a derivative with R² beingthiocarbamoylated.

In this reaction, preferably, the amine is used in an amount of oneequivalent to an excess amount. The reaction proceeds in a good yield ina solvent (for example, toluene, benzene, xylene, or DMF) at atemperature in the range of from 20 to 100° C., and the reaction time isabout 30 min to 24 hr.

Besides the methods (1) to (5), for example, introduction of a modifyinggroup by alkoxyalkylation, sulfonylation or the like under basicconditions and, in addition, the conventional substitution reaction formodifying a hydroxyl group, such as an acetal modification reaction,without creating side reactions, such as cleavage of a lactam ring,allyl rearrangement, and elimination, even under acidic conditionsthrough selection of suitable conditions permit the introduction of R².

In the novel skeleton wherein R⁵ represents a hydrogen atom, among thecompounds represented by the formula (VII), both the 6- and 7-positionsare a free secondary hydroxyl group. One of the hydroxyl groups is ahydroxyl group at the allyl position. Therefore, two hydroxyl groups maybe freely modified by quite the same manner as used in the modificationof a hydroxyl group in the prior application (WO 97/30040) utilizing thedifference in reactivity.

Further, for the fundamental skeleton represented by the formulae (V)and (IX), for example, the alkylation of the hydroxyl group at the6-position causes the side chain at the 7-position to undergo hydrolysisor alkylation under the reaction conditions. Thus, the modification ofthe hydroxyl group at the 6-position in the above manner leads to a fearof affecting the side chain at the 7-position. Therefore, when themodification cannot be directly carried out, the adoption of the abovemethod is very effective. Further, the above method is useful also inthe case where, in the synthesis of the compound represented by theformula (I) (wherein R¹ is as defined above in the formula (I), R² is asdefined above in the formula (I) excluding the hydrogen atom, and Rrepresents a hydroxyl group) by the protection of the hydroxyl group atthe 7-position and the deprotection, a desired compound cannot beprepared due to rearrangement between the 6- and 7-positions dependingupon reaction conditions or the type of the side chain. Further, alsowhen the compound represented by the formula (VI) is used as thestarting compound, the 7-position can be converted in quite the samemanner as described above.

Compounds Represented by the Formula (II)/Intermediates for Synthesis

The present invention provides compounds represented by the formula (II)or pharmaceutically acceptable salts thereof. These compounds are usefulas an intermediate for the synthesis of the compounds represented by theformula (I). Therefore, in the formula, R¹ is as defined above in R¹ inthe formula (I), and preferred examples thereof also include thosedescribed above in R in the formula (I).

EXAMPLES Example 1

Compound Represented by Formula (IV) wherein R¹ Represents Methyl

A compound represented by the formula (III) (200 mg=0.76 mmol) wasdissolved in methylene chloride (4 ml), and the solution was cooled to-15° C. Methanesulfonyl chloride (88 μl=1.15 mmol) was added thereto inthe presence of diisopropylethylamine (266 μl=1.53 mmol), and themixture was stirred for 15 min. Methylene chloride (20 ml) was addedthereto, the mixture was washed with saturated saline (20 ml), and thesolvent was removed under reduced pressure. A 2 M methylamine/THFsolution (2.29 ml) was added to the reaction product, and the mixturewas stirred at room temperature for one hr. The solvent was removedunder reduced pressure to give the title crude compound (209 mg, 100%).The compound thus prepared, due to its instability, was immediately usedto the next reaction without purification.

Example 2

(4aR,5R,6R,7R)-7-Acetoxy-6-hydroxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (100 mg=0.36 mmol) prepared in Example 1 was dissolved inacetonitrile (5 ml), acetic acid (200 μl=3.30 mmol) was added to thesolution, and the mixture was stirred at room temperature for 20 hr.Methylene chloride (20 ml) was added to the reaction solution, themixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (20 ml×2) and saturated saline (20 ml), and the organic phasewas dried over sodium sulfate. The solvent was removed under reducedpressure, and the residue was purified by preparative TLC to give thetitle compound (85 mg, 74%).

¹ H NMR (CDCl₃) δ 1.14 (3H, s, 4a-CH₃), 1.20 (3H, d, J=7.2 Hz, 5-CH₃),1.88 (3H, d, J=2.0 Hz, 3-CH₃), 1.90 (1H, dq, J=7.2, 2.9 Hz, 5-H), 2.06(3H, s, OCOCH₃), 2.16 (1H, br d, J=16.0 Hz, 4-H), 2.82 (1H, d, J=16.0Hz, 4-H), 3.10(3H, s, N--CH₃), 3.84 (1H, m, 6-H), 5.20 (1H, dd, J=4.8,1.7 Hz, 7-H), 5.70 (1H, d, J=4.8 Hz, 8-H), 5.75 (1H, s, 9-H); MS (EI)m/z 317 (M)⁺ ; [α]¹⁸ _(D) -608° (c 1.0, MeOH); mp 50-55° C.

Example 3

(4aR,5R,6R,7R)-7-Acetoxy-6-propionyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (22 mg=0.07 mmol) prepared in Example 2 was dissolved inpyridine (1 ml), propionyl chloride (21 μl=0.35 mmol) was added to thesolution, and the mixture was stirred at room temperature for 24 hr.Methylene chloride (20 ml) was added to the reaction mixture, themixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (20 ml×2) and saturated saline (20 ml), and the solvent wasremoved under reduced pressure. The organic phase was dried over sodiumsulfate, and the solvent was removed under reduced pressure. The residuewas purified by preparative TLC to give the title compound (6 mg, 23%).

¹ H NMR (CDCl₃) δ 1.09 (3H, d, J=7.2 Hz, 5-CH₃), 1.11 (3H, s, 4a-CH₃),1.14 (3H, t, J=7.6 Hz, OCOCH₂ CH₃ ), 1.88 (3H, d, J=1.9 Hz, 3-CH₃), 2.05(3H, s, OCOCH₃), 2.10 (1H, dq, J=7.2, 2.8 Hz, 5-H), 2.17 (1H, br d,J=15.9 Hz, 4-H), 2.34 (2H, q, J=7.6 Hz, OCOCH₂ CH₃), 2.83 (1H, d, J=15.9Hz, 4-H), 3.10 (3H, s, N--CH₃), 5.08 (1H, m, 6-H), 5.13 (1H, dd, J=4.7,1.6 Hz, 7-H), 5.73 (1H, s, 9-H), 5.76 (1H, d, J=4.7 Hz, 8-H); MS(FAB)m/z 374 (M+H)⁺ ; [α]²⁰ _(D) -291° (c 1.0, MeOH).

Example 4

(4aR,5R,6R,7R)-7-Acetoxy-6-(2-furancarbonyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

In the same manner as in Example 3, the compound (10 mg=0.03 mmol)prepared in Example 2 was dissolved in pyridine (1 ml), 2-furoylchloride (9 μl=0.09 mmol) was added to the solution, and the mixture wasstirred at room temperature for 15 hr. Methylene chloride (20 ml) wasadded to the reaction mixture, the mixture was washed with a saturatedaqueous sodium hydrogencarbonate solution (20 ml×2) and saturated saline(20 ml), and the solvent was removed under reduced pressure. The organicphase was dried over sodium sulfate, and the solvent was removed underreduced pressure. The residue was purified by preparative TLC to givethe title compound (6 mg, 49%).

¹ H NMR (CDCl₃) δ 1.15 (3H, d, J=7.2 Hz, 5-CH₃), 1.21 (3H, s, 4a-CH₃),1.89 (3H, d, J=1.9 Hz, 3-CH₃), 2.07 (3H, s, OCOCH₃), 2.20 (1H, dq,J=7.2, 2.8 Hz, 5-H), 2.21 (1H, br d, J=15.9 Hz, 4-H), 2.86 (1H, d,J=15.9 Hz, 4-H), 3.11 (3H, s, N--CH₃), 5.26 (1H, dd, J=4.7, 1.6 Hz,7-H), 5.29 (1H, m, 6-H), 5.76 (1H, s, 9-H), 5.80 (1H, d, J=4.7 Hz, 8-H),6.49 (1H, dd, J=3.5, 1.7 Hz, OCOC₄ H₃ O), 7.12 (1H, dd, J=3.5, 0.8 Hz,OCOC₄ H₃ O), 7.57 (1H, dd, J=1.7, 0.8 Hz, OCOC₄ H₃ O); MS (EI)m/z 411(M)⁺ ; [α]²⁰ _(D) -269° (c 0.6, MeOH).

Example 5

(4aR,5R,6R,7R)-7-Acetoxy-6-(imidazol-1-ylcarbonyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (100 mg=0.32 mmol) prepared in Example 2 was dissolved inmethylene chloride (3 ml), 1,1'-carbonyldiimidazole (204 mg=1.26 mmol)was added to the solution, and the mixture was stirred at roomtemperature for 17 hr. Methylene chloride was added to the reactionmixture, the mixture was washed with water, and the organic phase wasdried over sodium sulfate. The solvent was removed under reducedpressure, and the residue was purified by column chromatography onsilica gel to give the title compound (130 mg, 100%).

¹ H NMR (CDCl₃) δ 1.19 (3H, s, 4a-CH₃), 1.22 (3H, d, J=7.1 Hz, 5-CH₃),1.91 (3H, d, J=1.9 Hz, 3-CH₃), 2.11 (3H, s, OCOCH₃), 2.25 (1H, br d,J=16.0 Hz, 4-H), 2.27 (1H, dq, J=7.1, 3.0 Hz, 5-H), 2.89 (1H, d, J=16.0Hz, 4-H), 3.13 (3H, s, N--CH₃), 5.26 (1H, m, 6-H), 5.38 (1H, dd, J=4.8,1.5 Hz, 7-H), 5.77(1H, d, J=4.8 Hz, 8-H), 5.78 (1H, s, 9-H), 7.09 (1H,br s, OCOC₃ N₂), 7.39 (1H, br s, OCOC₃ N₂),8.10 (1H, br s, OCOC₃ N₂); MS(TSP) m/z 412(M+H)⁺.

Example 6

(4aR,5R,6R,7R)-7-Acetoxy-6-(pyrrolidin-1-ylcarbonyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (20 mg=0.05 mmol) prepared in Example 5 was dissolved intoluene (0.5 ml), pyrrolidine (20 μl=0.24 mmol) was added to thesolution, the mixture was stirred at room temperature for 2 hr. Ethylacetate was added to the reaction mixture, the mixture was washed withwater, and the organic phase was dried over sodium sulfate. The solventwas removed under reduced pressure, and the residue was purified bycolumn chromatography on silica gel to give the title compound (15 mg,75%).

¹ H NMR (CDCl₃) δ 1.13 (3H, s, 4a-CH₃), 1.16 (3H, d, J=7.1 Hz, 5-CH₃),1.83-1.90 (4H, m, OCOC₄ H₈ N), 1.90 (3H, d, J=1.9 Hz, 3-CH₃), 2.05 (3H,s, OCOCH₃), 2.12 (1H, dq, J=7.1, 3.0 Hz, 5-H), 2.19 (1H, br d, J=16.5Hz, 4-H), 2.85 (1H, d, J=16.5 Hz, 4-H), 3.11 (3H, s, N--CH₃), 3.18-3.51(4H, m, OCOC₄ H₈ N), 4.98 (1H, m, 6-H), 5.23 (1H, dd, J=4.8, 1.5 Hz,7-H), 5.75 (1H, s, 9-H), 5.81 (1H, d, J=4.8 Hz, 8-H); MS (FAB) m/z 415(M+H)⁺.

Example 7

(4aR,5R,6R,7R)-6-Hydroxy-7-propionyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (100 mg=0.36 mmol) prepared in Example 1 was dissolved inacetonitrile(5 ml), propionic acid (270 μl=3.60 mmol) was added to thesolution, and the mixture was stirred at room temperature for 20 hr.Methylene chloride (20 ml) was added to the reaction mixture, themixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (20 ml×2) and saturated saline (20 ml), and the organic phasewas dried over sodium sulfate. The solvent was removed under reducedpressure, and the residue was purified by preparative TLC to give thetitle compound (68 mg, 57%).

¹ H NMR (CDCl₃) δ 1.12 (3H, t, J=7.5 Hz, OCOCH₂ CH₃ ), 1.13 (3H, s,4a-CH₃), 1.19 (3H, d, J=7.2 Hz, 5-CH₃), 1.87 (3H, d, J=2.0 Hz, 3-CH₃),1.88 (1H, dq, J=7.2, 2.9 Hz, 5-H), 2.15(1H, br d, J=16.0 Hz, 4-H), 2.31(1H, ap q, J=7.5 Hz, OCOCH₂ CH₃), 2.34 (1H, ap q,J=7.5 Hz, OCOCH₃ CH₃),2.81 (1H, d, J=16.0 Hz, 4-H), 3.09(3H, s, N--CH₃), 3.81 (1H, m, 6-H),5.21 (1H,dd, J=4.8, 1.7 Hz, 7-H), 5.70 (1H, d, J=4.8 Hz, 8-H), 5.75 (1H,s, 9-H); MS (EI)m/z 331 (M)⁺.

Example 8

(4aR,5R,6R,7R)-6,7-Dipropionyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (27 mg=0.08 mmol) prepared in Example 7 was dissolved inpyridine (1 ml), propionyl chloride (25 μl=0.40 mmol) was added to thesolution, and the mixture was stirred at room temperature for 24 hr.Methylene chloride (20 ml) was added to the reaction mixture, themixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (20 ml×2) and saturated saline (20 ml), and the solvent wasremoved under reduced pressure. The organic phase was dried over sodiumsulfate, and the solvent was removed under reduced pressure. The residuewas purified by preparative TLC to give the title compound (14 mg, 45%).

¹ H NMR (CDCl₃) δ 1.08 (3H, d, J=7.2 Hz, 5-CH₃), 1.10 (3H, s,4a-CH₃),1.12 (3H, t, J=7.5 Hz, OCOCH₂ CH₃ ), 1.13 (3H, t, J=7.6 Hz,OCOCH₂ CH₃ ), 1.87 (3H, d, J=1.9 Hz, 3-CH₃), 2.09(1H, dq, J=7.2, 2.8 Hz,5-H), 2.16 (1H, br d, J=15.9 Hz, 4-H), 2.30 (1H, ap q,J=7.5 Hz, OCOCH₂CH₃), 2.31 (1H, ap q,J=7.5 Hz, OCOCH₂ CH₃), 2.34 (2H, q, J=7.6 Hz,OCOCH₂ CH₃), 2.82 (1H, d, J=15.9 Hz, 4-H), 3.09 (3H, s, N--CH₃), 5.07(1H, m, 6-H), 5.13 (1H, dd, J=4.7, 1.6 Hz, 7-H), 5.73 (1H, s, 9-H), 5.76(1H, d, J=4.7 Hz, 8-H); MS (FAB)m/z 388 (M+H)⁺ ; [α]¹⁸ _(D) -454° (c1.0, MeOH).

Example 9

(4aR,5R,6R,7R)-6-(2-Furancarbonyloxy)-7-propionyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (25 mg=0.08 mmol) prepared in Example 7 was dissolved inpyridine (1 ml), 2-furoyl chloride (22 μl=0.23 mmol) was added to thesolution, and the mixture was stirred at room temperature for 19 hr.Methylene chloride (20 ml) was added to the reaction mixture, and themixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (20 ml×2) and saturated saline (20 ml). The solvent was removedunder reduced pressure. The organic phase was dried over sodium sulfate,and the solvent was removed under reduced pressure. The residue waspurified by preparative TLC to give the title compound (12 mg, 37%).

¹ H NMR (CDCl₃) δ 1.12 (3H, t, J=7.5 Hz, OCOCH₂ CH₃ ), 1.14 (3H, d,J=7.2 Hz, 5-CH₃), 1.20 (3H, s, 4a-CH₃), 1.88 (3H, d, J=1.9 Hz, 3-CH₃),2.19 (1H, dq, J=7.2, 2.8 Hz, 5-H), 2.20 (1H, br d, J=15.9 Hz, 4-H), 2.33(1H, ap q, J=7.5 Hz, OCOCH₂ CH₃), 2.34 (1H, ap q,J=7.5 Hz, OCOCH₂ CH₃),2.85 (1H, d, J=15.9 Hz, 4-H), 3.10 (3H, s, N--CH₃), 5.27 (1H, m, 7-H),5.27 (1H, m, 6-H), 5.76 (1H, s, 9-H), 5.80 (1H, d, J=4.7 Hz, 8-H), 6.49(1H, dd, J=3.5, 1.7 Hz, OCOC₄ H₃ O), 7.12 (1H, dd, J=3.5, 0.8 Hz, OCOC₄H₃ O), 7.57 (1H, dd, J=1.7, 0.8 Hz, OCOC₄ H₃ O); MS (FAB) m/z 426 (M+H)⁺; [α]¹⁸ _(D) -245° (c 1.0, MeOH).

Example 10

(4aR,5R,6R,7R)-6,7-Dihydroxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (100 mg=0.32 mmol) prepared in Example 2 was dissolved inacetonitrile (5 ml), water (5 ml) was added to the solution, and themixture was stirred at room temperature for 20 hr. Methylene chloride(20 ml) was added thereto, and the mixture was washed with saturatedsaline (20 ml), and the organic phase was dried over sodium sulfate. Thesolvent was removed under reduced pressure, and the residue was purifiedby preparative TLC to give the title compound (63 mg, 71%).

¹ H NMR (CDCl₃) δ 1.11 (3H, s, 4a-CH₃), 1.20 (3H, d, J=7.2 Hz, 5-CH₃),1.86 (3H, d, J=1.9 Hz, 3-CH₃), 1.94 (1H, dq, J=7.2, 2.5 Hz, 5-H), 2.08(1H, br d, J=15.9 Hz, 4-H), 2.80 (1H, d, J=15.9 Hz, 4-H), 3.10 (3H, s,N--CH₃), 3.87 (1H, m, 6-H), 4.17 (1H, dd, J=4.8, 1.9 Hz, 7-H), 5.73 (1H,s, 9-H), 5.80 (1H, d, J=4.8 Hz, 8-H); MS (EI) m/z 275 (M)⁺ ; [α]²⁰ _(D)-455° (c 0.2, MeOH).

Example 11

(4aR,5R,6R,7R)-7-(t-Butyldimethylsilyloxy)-6-hydroxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (200 mg=0.73 mmol) prepared in Example 10 was dissolved inDMF (10 ml), t-butyldimethylsilyl chloride (650 mg=4.31 mmol) was addedto the solution in the presence of imidazole (500 mg=7.34 mmol), and themixture was stirred at room temperature for 15 hr. Ethyl acetate wasadded to the reaction mixture, the mixture was washed with water, andthe organic phase was dried over sodium sulfate. The solvent was removedunder reduced pressure, and the residue was purified by columnchromatography on silica gel to give the title compound (282 mg, 100%).

¹ H NMR (CDCl₃) δ 0.10 (3H, s, OTBDMS), 0.11 (3H, s, OTBDMS), 0.89 (9H,s, OTBDMS), 1.11 (3H, s, 4a-CH₃), 1.19 (3H, d, J=7.3 Hz, 5-CH₃), 1.88(3H, d, J=1.9 Hz, 3-CH₃), 2.02 (1H, dq, J=7.3, 2.3 Hz, 5-H), 2.17 (1H,br d, J=15.7 Hz, 4-H), 2.79 (1H, d, J=15.7 Hz, 4-H), 3.11 (3H, s,N--CH₃), 3.74 (1H, m, 6-H), 4.16 (1H, dd, J=4.8, 2.1 Hz, 7-H), 5.56 (1H,d, J=4.8 Hz, 8-H), 5.75 (1H, s, 9-H); MS (TSP) m/z 390 (M+H)⁺.

Example 12

(4aR,5R,6R,7R)-6-Acetoxy-7-hydroxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 3 was repeated, except that the compound (20mg=0.05 mmol) prepared in Example 11 was dissolved in methylene chloride(1 ml), acetyl chloride (18 μl=0.25 mmol) was added to the solution inthe presence of pyridine (42 μl=0.52 mmol), and the mixture was stirredat room temperature for 17 hr. Thus, a corresponding acetyl compound (12mg, 55%) was prepared.

This compound (12 mg=0.03 mmol) was dissolved in THF (1 ml), a 1 Mtetrabutylammonium fluoride/THF solution (50 μl=0.05 mmol) was added tothe solution, and the mixture was stirred at room temperature for 2 hr.Ethyl acetate was added to the reaction mixture, the mixture was washedwith water, and the organic phase was dried over sodium sulfate. Thesolvent was removed under reduced pressure, and the residue was purifiedby preparative TLC to give the title compound (3 mg, 34%).

¹ H NMR (CDCl₃) δ 1.10 (3H, s, 4a-CH₃), 1.11 (3H, d, J=7.2 Hz, 5-CH₃),1.89 (3H, d, J=2.0 Hz,3-CH₃), 2.08 (3H, s, OCOCH₃), 2.14 (1H, br d,J=15.8 Hz, 4-H), 2.15 (1H, dq, J=7.2, 2.8 Hz, 5-H), 2.83 (1H, d, J=15.8Hz, 4-H), 3.12 (3H, s, N--CH₃), 4.15 (1H, m, 7-H), 4.95 (1H, m, 6-H),5.74 (1H, s, 9-H), 5.77 (1H, d, J=4.6 Hz, 8-H); MS (TSP) m/z 318 (M+H)⁺.

Example 13

(4aR,5R,6R,7R)-7-Hydroxy-6-propionyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 3 was repeated, except that the compound (25mg=0.06 mmol) prepared in Example 11 was dissolved in methylene chloride(1 ml), propionyl chloride (28 μl=0.28 mmol) was added to the solutionin the presence of pyridine (52 μl=0.64 mmol), and the mixture wasstirred at room temperature for 17 hr. Thus, a corresponding propionylcompound (7 mg, 25%) was prepared.

The procedure of Example 12 was repeated, except that the compound (10mg=0.02 mmol) prepared just above was dissolved in THF (1 ml), a 1 Mtetrabutylammonium fluoride/THF solution (50 μl=0.05 mmol) was added tothe solution, and the mixture was stirred at room temperature for 2 hr.Thus, the title compound (1.4 mg, 34%) was prepared.

¹ H NMR (CDCl₃) δ 1.10 (3H, s, 4a-CH₃), 1.11 (3H, d, J=7.1 Hz, 5-CH₃),1.15 (3H, t, J=7.6 Hz, OCOCH₂ CH₃ ), 1.89 (3H, d, J=2.0 Hz, 3-CH₃), 2.16(1H, br d, J=15.0 Hz, 4-H), 2.16 (1H, dq, J=7.1, 3.1 Hz, 5-H), 2.35 (1H,q, J=7.6 Hz, OCOCH₂ CH₃), 2.36 (1H, q, J=7.6 Hz, OCOCH₂ CH₃), 2.82 (1H,d, J=15.0 Hz, 4-H), 3.12 (3H, s, N--CH₃), 4.14 (1H, dd, J=4.6, 1.2 Hz,7-H), 4.96 (1H, m, 6-H), 5.74 (1H, s, 9-H), 5.77 (1H, d, J=4.6 Hz, 8-H);MS (TSP) m/z 332 (M+H)⁺.

Example 14

(4aR,5R,6R,7R)-6-Cyclopropylcarbonyloxy-7-hydroxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (17 mg=0.05 mmol) prepared in Example 27 was dissolved inacetonitrile (0.3 ml), 1 N hydrochloric acid (0.17 ml=0.17 mmol) wasadded to the solution, and the mixture was stirred at room temperaturefor 30 min. Methylene chloride was added to the reaction mixture, andthe mixture was washed with a saturated aqueous sodium hydrogencarbonatesolution. The organic phase was dried over sodium sulfate. The solventwas removed under reduced pressure, and the residue was purified bypreparative TLC to give the title compound (10 mg, 60%).

¹ H NMR (CDCl₃) δ 0.79-0.96 (4H, m, OCOC₃ H₅), 1.04 (3H, s, 4a-CH₃),1.05 (3H, d, J=7.1 Hz, 5-CH₃), 1.53 (1H, m, OCOC₃ H₅), 1.82 (3H, d,J=2.0 Hz, 3-CH₃), 2.08 (1H, dq, J=7.1, 2.9 Hz, 5-H), 2.09 (1H, br d,J=16.0 Hz, 4-H), 2.76 (1H, d, J=16.0 Hz, 4-H), 3.05 (3H, s, N--CH₃),4.07 (1H, br d, J=4.0 Hz, 7-H), 4.87 (1H, m, 6-H), 5.68 (1H, s, 9-H),5.70 (1H, d, J=4.0 Hz, 8-H); MS (TSP) m/z 344 (M+H)⁺.

Example 15

(4aR,5R,6R,7R)-6-Cyclohexylcarbonyloxy-7-hydroxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 3 was repeated, except that the compound (100mg=0.26 mmol) prepared in Example 11 was dissolved in methylene chloride(3 ml), cyclohexanecarbonyl chloride (80 μl=0.60 mmol) was added to thesolution in the presence of pyridine (80 μl=0.99 mmol), and the mixturewas stirred at room temperature for 4 hr. Thus, a correspondingcyclohexylcarbonyl compound (62 mg, 48%) was prepared.

The procedure of Example 12 was repeated, except that the compound (60mg=0.12 mmol) prepared just above was dissolved in THF (2 ml), a 1 Mtetrabutylammonium fluoride/THF solution (0.30 ml=0.30 mmol) was addedthereto, and the mixture was stirred at room temperature for one hr.After the purification by preparative TLC, the title compound (31 mg,66%) was obtained.

¹ H NMR (CDCl₃) δ 1.21-1.86 (10H, m, OCOC₆ H₁₁), 1.10 (3H, d, J=7.2 Hz,5-CH₃), 1.11 (3H, s, 4a-CH₃), 1.89 (3H, d, J=1.7 Hz, 3-CH₃), 2.31 (1H,m, OCOC₆ H₁₁), 2.16 (1H, dq, J=7.2, 2.8 Hz, 5-H), 2.16 (1H, br d, J=15.4Hz, 4-H), 2.82 (1H, d, J=15.4 Hz, 4-H), 3.12 (3H, s, N--CH₃), 4.09 (1H,dd, J=4.5, 1.2 Hz, 7-H), 4.95 (1H, m, 6-H), 5.75 (1H, s, 9-H), 5.77 (1H,d, J=4.5 Hz, 8-H); MS (TSP) m/z 386 (M+H)⁺.

Example 16

(4aR,5R,6R,7R)-6-Benzoyloxy-7-hydroxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 3 was repeated, except that the compound (30mg=0.08 mmol) prepared in Example 11 was dissolved in methylene chloride(1.5 ml), benzoyl chloride (45 μl=0.39 mmol) was added to the solutionin the presence of pyridine (62 μl=0.77 mmol), and the mixture wasstirred at room temperature for 17 hr. Thus, a corresponding benzoylcompound (16 mg, 41%) was prepared.

The procedure of Example 12 was repeated, except that the compound (16mg=0.03 mmol) prepared above was dissolved in THF (1 ml), a 1 Mtetrabutylammonium fluoride/THF solution (50 μl=0.05 mmol) was addedthereto, and the mixture was stirred at room temperature for 30 min.Thus, the title compound (4 mg, 34%) was prepared.

¹ H NMR (CDCl₃) δ 1.20 (3H, d, J=7.1 Hz, 5-CH₃), 1.25 (3H, s, 4a-CH₃),1.91 (3H, d, J=1.9 Hz, 3-CH₃), 2.23 (1H, br d, J=16.0 Hz, 4-H), 2.29(1H, dq, J=7.1, 3.1 Hz, 5-H), 2.88 (1H, d, J=16.0 Hz, 4-H), 3.13 (3H, s,N--CH₃), 4.31 (1H, dd, J=4.4, 1.2 Hz, 7-H), 5.22 (1H, m,6-H), 5.78 (1H,s, 9-H), 5.81 (1H, d, J=4.4 Hz, 8-H), 7.43-8.01 (5H, m, OCOC₆ H₅); MS(FAB) m/z 380 (M+H)⁺.

Example 17

(4aR,5R,6R,7R)-6-(2-Furancarbonyloxy)-7-hydroxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 3 was repeated, except that the compound (25mg=0.06 mmol) prepared in Example 11 was dissolved in methylene chloride(1 ml), 2-furoyl chloride (32 μl=0.32 mmol) was added to the solution inthe presence of pyridine (52 μl=0.64 mmol), and the mixture was stirredat room temperature for 17 hr. Thus, a 2-furoyl compound (23 mg, 77%)was prepared.

The procedure of Example 12 was repeated, except that the compound (15mg=0.03 mmol) prepared just above was dissolved in THF (1.5 ml), a 1 Mtetrabutylammonium fluoride/THF solution (50 μl=0.05 mmol) was added tothe solution, and the mixture was stirred at room temperature for 30min. Thus, the title compound (5 mg, 41%) was prepared.

¹ H NMR (CDCl₃) δ 1.17 (3H, d, J=7.2 Hz, 5-CH₃), 1.22 (3H, s, 4a-CH₃),1.90 (3H, d, J=2.0 Hz, 3-CH₃), 2.21 (1H, br d, J=16.0 Hz, 4-H), 2.36(1H, dq, J=7.2, 2.9 Hz, 5-H), 2.86 (1H, d, J=16.0 Hz, 4-H), 3.13 (3H, s,N--CH₃), 4.29 (1H, m, 7-H), 5.17 (1H, m, 6-H), 5.77 (1H, s, 9-H), 5.80(1H, d, J=4.9 Hz, 8-H), 6.51 (1H, dd, J=3.5, 1.6 Hz, OCOC₄ H₃ O), 7.13(1H, dd, J=3.5, 0.7 Hz, OCOC₄ H₃ O), 7.59 (1H, dd, J=1.6, 0.7 Hz, OCOC₄H₃ O); MS (FAB) m/z 370 (M+H)⁺.

Example 18

(4aR,5R,6R,7R)-6-Butoxy-7-hydroxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 14 was repeated, except that the compound (20mg=0.05 mmol) prepared in Example 37 was dissolved in acetonitrile (0.4ml), a 1 N hydrochloric acid (0.20 ml=0.20 mmol) was added to thesolution, and a mixture was stirred at room temperature for 30 min.Thus, the title compound (13 mg, 68%) was prepared.

¹ H NMR (CDCl₃) δ 0.88 (3H, t, J=7.2 Hz, OCH₂ CH₂ CH₂ CH₃), 1.05 (3H, s,4a-CH₃), 1.14 (3H, d, J=7.1 Hz, 5-CH₃), 1.34 (2H, m, OCH₂ CH₂ CH₂ CH₃),1.50 (2H, m, OCH₂ CH₂ CH₂ CH₃), 1.85 (3H, d, J=1.9 Hz, 3-CH₃), 1.88 (1H,dq, J=7.1, 2.8 Hz, 5-H), 1.99 (1H, br d, J=15.9 Hz, 4-H), 2.77 (1H, d,J=15.9 Hz, 4-H), 3.08 (3H, s, N--CH₃), 3.35 (1H, dt, J=9.2, 7.2 Hz, OCH₂CH₂ CH₂ CH₃), 3.35 (1H, m, 6-H), 3.62 (1H, dt, J=9.2, 7.2 Hz, OCH₂ CH₂CH₂ CH₃), 4.19 (1H, br s, 7-H), 5.69 (1H, s, 9-H), 5.78 (1H, d, J=4.7Hz, 8-H); MS (EI) m/z 331 (M)⁺ ; [α]²⁰ _(D) -168° (c 1.0, MeOH).

Example 19

(4aR,5R,6R,7R)-7-Hydroxy-6-(3-methylbutoxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 14 was repeated, except that the compound (35mg=0.10 mmol) prepared in Example 38 was dissolved in acetonitrile (0.7ml), a 1 N hydrochloric acid (0.35 ml=0.35 mmol) was added to thesolution, and the mixture was stirred at room temperature for 30 min.Thus, the title compound (22 mg, 65%) was prepared.

¹ H NMR (CDCl₃) δ 0.85 (3H, d, J=6.6 Hz, OCH₂ CH₂ CH(CH₃)₂), 0.86 (3H,d, J=6.6 Hz, OCH₂ CH₂ CH(CH₃)₂), 1.03 (3H, s, 4a-CH₃), 1.13 (3H, d,J=7.1 Hz, 5-CH₃), 1.40 (2H, m, OCH₂ CH₂ CH(CH₃)₂), 1.66 (1H, m, OCH₂ CH₂CH(CH₃)₂), 1.83 (3H, d, J=1.9 Hz, 3-CH₃), 1.87 (1H, dq, J=7.1, 2.8 Hz,5-H), 1.96 (1H, br d, J=15.9 Hz, 4-H), 2.75 (1H, d, J=15.9 Hz, 4-H),3.07 (3H, s, N--CH₃), 3.35 (1H, m, 6-H), 3.36 (1H, dt, J=9.3, 6.6 Hz,OCH₂ CH₂ CH(CH₃)₂), 3.63 (1H, dt, J=9.3, 6.6 Hz, OCH₂ CH₂ CH(CH₃)₂),4.19 (1H, br s, 7-H), 5.68 (1H, s, 9-H), 5.77 (1H, d, J=4.7 Hz, 8-H); MS(EI) m/z 345 (M)⁺ ; [α]²⁰ _(D) -102° (c 0.7, MeOH).

Example 20

(4aR,5R,6R,7R)-6-Cyclopropylmethoxy-7-hydroxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 14 was repeated, except that the compound (15mg=0.04 mmol) prepared in Example 40 was dissolved in acetonitrile (0.3ml), a 1 N hydrochloric acid (0.15 ml=0.15 mmol) was added to thesolution, and the mixture was stirred at room temperature for 30 min.Thus, the title compound (7 mg, 49%) was prepared.

¹ H NMR (CDCl₃) δ 0.19-0.47 (4H, m, OCH₂ C₃ H₅), 1.01 (1H, m, OCH₂ C₃H₅), 1.08 (3H, s, 4a-CH₃), 1.16 (3H, d, J=7.1 Hz, 5-CH₃), 1.86 (3H, d,J=1.9 Hz, 3-CH₃), 1.89 (1H, dq, J=7.1, 2.8 Hz, 5-H), 2.03 (1H, br d,J=15.9 Hz, 4-H), 2.78 (1H, d, J=15.9 Hz, 4-H), 3.09 (3H, s, N--CH₃),3.29 (1H, dd, J=10.3, 6.5 Hz, OCH₂ C₃ H₅), 3.42 (1H, m, 6-H), 3.46 (1H,dd, J=10.3, 6.5 Hz, OCH₂ C₃ H₅), 4.20 (1H, br s, 7-H), 5.70 (1H, s,9-H), 5.79 (1H, d, J=4.7 Hz, 8-H); MS (EI) m/z 329 (M)⁺ ; [α]²⁰ _(D)-149° (c 1.0, MeOH).

Example 21

(4aR,5R,6R,7R)-7-Hydroxy-6-(2-propenyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 14 was repeated, except that the compound (20mg=0.06 mmol) prepared in Example 41 was dissolved in acetonitrile (0.4ml), 1 N hydrochloric acid (0.20 ml=0.20 mmol) was added to thesolution, and the mixture was stirred at room temperature for 30 min.Thus, the title compound (16 mg, 85%) was prepared.

¹ H NMR (CDCl₃) δ 1.07 (3H, s, 4a-CH₃), 1.15 (3H, d, J=7.1 Hz, 5-CH₃),1.84 (3H, d, J=1.9 Hz, 3-CH₃), 1.90 (1H, dq, J=7.1, 2.8 Hz, 5-H), 1.99(1H, br d, J=15.9 Hz, 4-H), 2.73 (1H, d, J=15.9 Hz, 4-H), 3.08 (3H, s,N--CH₃), 3.45 (1H, m, 6-H), 3.95 (1H, ddt, J=13.1, 5.5, 1.5 Hz, OCH₂CHCH₂), 4.15 (1H, ddt, J=13.1, 5.5, 1.5 Hz, OCH₂ CHCH₂), 4.20 (1H, br s,7-H), 5.12 (1H, ddt, J=17.2, 10.4, 1.5 Hz, OCH₂ CHCH₂), 5.23 (1H, ddt,J=17.2, 10.4, 1.5 Hz, OCH₂ CHCH₂), 5.69 (1H, s, 9-H), 5.78 (1H, d, J=4.7Hz, 8-H), 5.88 (1H, ddt, J=17.2, 10.4, 5.5 Hz, OCH₂ CHCH₂); MS (EI) m/z315 (M)⁺ ; [α]²⁰ _(D) -224° (c 1.0, MeOH).

Example 22

(4aR,5R,6R,7R)-7-Hydroxy-6-propylcarbamoyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (34mg=0.08 mmol) prepared in Example 5 was dissolved in toluene (1 ml),propylamine (33 μl=0.40 mmol) was added to the solution, and the mixturewas stirred at room temperature for 3.5 hr. Thus, a correspondingpropylcarbamoyl compound was prepared (20 mg, 61%).

This compound (20 mg=0.05 mmol) was dissolved in a solution of1,4-dioxane (0.5 ml) in water (0.2 ml), a 1 N aqueous sodium hydroxidesolution (49 μl=0.05 mmol) was added to the solution, and the mixturewas stirred at room temperature for 15 hr. Ethyl acetate was added tothe reaction mixture, the mixture was washed with water, and the organicphase was dried over sodium sulfate. The solvent was removed underreduced pressure, and the residue was purified by column chromatographyon silica gel to give the title compound (14 mg, 82%).

¹ H NMR (CDCl₃) δ 0.92 (3H, t, J=7.3 Hz, OCONHCH₂ CH₂ CH₃), 1.04 (3H, s,4a-CH₃), 1.12 (3H, d, J=7.0 Hz, 5-CH₃), 1.53 (2H, seq, J=7.3 Hz,OCONHCH₂ CH₂ CH₃), 1.88 (3H, d, J=1.6 Hz, 3-CH₃), 2.14 (1H, dq, J=7.0,2.8 Hz, 5-H), 2.15 (1H, br d, J=16.3 Hz, 4-H), 2.80 (1H, d, J=16.3 Hz,4-H), 3.10 (3H, s, N--CH₃), 3.15 (2H, br dt, J=7.3 Hz, OCONHCH₂ CH₂CH₃), 4.21 (1H, m, 7-H), 4.83 (2H, m, 6-H, OCONHCH₂ CH₂ CH₃), 5.74 (1H,s, 9-H), 5.78 (1H, d, J=4.5 Hz, 8-H); MS (TSP) m/z 361 (M+H)⁺.

Example 23

(4aR,5R,6R,7R)-7-Hydroxy-6-(pyrrolidin-1-ylcarbonyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 22 was repeated, except that the compound (15mg=0.04 mmol) prepared in Example 6 was dissolved in a solution of1,4-dioxane (0.5 ml) in water (0.2 ml), a 1 N aqueous sodium hydroxidesolution (36 μl=0.04 mmol) was added thereto, and the mixture wasstirred at room temperature for 15 hr. Thus, the title compound (12 mg,92%) was prepared.

¹ H NMR (CDCl₃) δ 1.09 (3H, s, 4a-CH₃), 1.15 (3H, d, J=7.1 Hz, 5-CH₃),1.85-1.89 (4H, m, OCOC₄ H₈ N), 1.90 (3H, d, J=1.9 Hz, 3-CH₃), 2.18 (1H,dq, J=7.1, 3.3 Hz, 5-H), 2.19 (1H, br d, J=16.6 Hz, 4-H), 2.81 (1H, d,J=16.6 Hz, 4-H), 3.12 (3H, s, N--CH₃), 3.19-3.51 (4H, m, OCOC₄ H₈ N),4.27 (1H, br d, J=4.5 Hz, 7-H), 4.80 (1H, m, 6-H), 5.75 (1H, s, 9-H),5.78 (1H, d, J=4.5 Hz, 8-H); MS (TSP) m/z 373 (M+H)⁺.

Example 24

(4aR,5R,6R,7R)-6-Hydroxy-7-methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

Methanol (10 ml) was added to the compound (100 mg=0.32 mmol) preparedin Example 2, and the mixture was stirred at 5° C. for 3 hr. The solventwas removed under reduced pressure, and the residue was purified bypreparative TLC to give the title compound (90 mg, 100%).

¹ H NMR (CDCl₃) δ 1.11 (3H, s, 4a-CH₃), 1.19 (3H, d, J=7.3 Hz, 5-CH₃),1.86 (3H, d, J=2.0 Hz, 3-CH₃), 1.91 (1H, dq, J=7.3, 2.6 Hz, 5-H), 2.13(1H, br d, J=16.0 Hz, 4-H), 2.78 (1H, d, J=16.0 Hz, 4-H), 3.09 (3H, s,N--CH₃), 3.43 (3H, s, O--CH₃), 3.70 (1H, dd, J=4.8, 1.9 Hz, 7-H), 3.91(1H, br s, 6-H), 5.74 (1H, s, 9-H), 5.82 (1H, d, J=4.8 Hz, 8-H); MS (EI)m/z 289 (M)⁺ ; [α]¹⁸ _(D) -584° (c 0.8, MeOH); mp 165-170° C.

Example 25

(4aR,5R,6R,7R)-6-Acetoxy-7-methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (20 mg=0.07 mmol) prepared in Example 24 was dissolved inpyridine (1 ml), acetyl chloride (15 μl=0.21 mmol) was added to thesolution, and the mixture was stirred at room temperature for 24 hr.Methylene chloride (20 ml) was added to the reaction mixture, themixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (20 ml×2) and saturated saline (20 ml), and the solvent wasremoved under reduced pressure. The organic phase was dried over sodiumsulfate, and the solvent was removed under reduced pressure. The residuewas purified by preparative TLC to give the title compound (12 mg, 53%).

¹ H NMR (CDCl₃) δ 1.08 (3H, s, 4a-CH₃), 1.08 (3H, d, J=7.2 Hz, 5-CH₃),1.86 (3H, d, J=1.9 Hz, 3-CH₃), 2.06 (3H, s, OCOCH₃ ), 2.08 (1H, dq,J=7.2, 2.8 Hz, 5-H), 2.12 (1H, br d, J=15.9 Hz, 4-H), 2.79 (1H, d,J=15.9 Hz, 4-H), 3.09 (3H, s,N--CH₃),3.49 (3H, s, O--CH₃), 3.60 (1H, dd,J=4.8, 1.3 Hz, 7-H), 5.08 (1H, m, 6-H), 5.72 (1H, s, 9-H), 5.74 (1H, d,J=4.8 Hz, 8-H); MS (EI) m/z 331 (M)⁺ ; [α]¹⁸ _(D) -291° (c 1.0, MeOH).

Example 26

(4aR,5R,6R,7R)-7-Methoxy-6-propionyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (14 mg=0.05 mmol) prepared in Example 24 was dissolved inpyridine (1 ml), propionyl chloride (7.4 μl=0.12 mmol) was added to thesolution, and the mixture was stirred at room temperature for 18 hr.Methylene chloride (20 ml) was added to the reaction mixture, and themixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (20 ml×2) and saturated saline (20 ml). The solvent was removedunder reduced pressure. The organic phase was dried over sodium sulfate,and the solvent was removed under reduced pressure. The residue waspurified by preparative TLC to give the title compound (5 mg, 30%).

¹ H NMR (CDCl₃) δ 1.08 (3H, d, J=7.2 Hz, 5-CH₃), 1.09 (3H, s, 4a-CH₃),1.14 (3H, t, J=7.5 Hz, OCOCH₂ CH₃ ), 1.87 (3H, d, J=1.9 Hz, 3-CH₃), 2.08(1H, dq, J=7.2, 2.8 Hz, 5-H), 2.13 (1H, br d, J=15.9 Hz, 4-H), 2.34 (2H,q, J=7.5 Hz, OCOCH₂ CH₃), 2.79 (1H, d, J=15.9 Hz, 4-H), 3.10 (3H, s,N--CH₃), 3.50 (3H, s, O--CH₃), 3.60 (1H, dd, J=4.8, 1.3 Hz, 7-H), 5.09(1H, m, 6-H), 5.73 (1H, s, 9-H), 5.75 (1H, d, J=4.8 Hz, 8-H); MS(FAB)m/z 346 (M+H)⁺ ; [α]¹⁸ _(D) -280° (c 0.6, MeOH).

Example 27

(4aR,5R,6R,7R)-6-Cyclopropylcarbonyloxy-7-methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (28 mg=0.10 mmol) prepared in Example 24 was dissolved inpyridine (1 ml), cyclopropylcarbonyl chloride (27 μl=0.29 mmol) wasadded to the solution, and the mixture was stirred at room temperaturefor 15 hr. Methylene chloride (20 ml) was added to the reaction mixture.The mixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (20 ml×2) and saturated saline (20 ml), and the solvent wasremoved under reduced pressure. The organic phase was dried over sodiumsulfate, and the solvent was removed under reduced pressure. The residuewas purified by preparative TLC to give the title compound (35 mg,100%).

¹ H NMR (CDCl₃) δ 0.83-1.04 (4H, m, OCOC₃ H₅), 1.09 (3H, d, J=7.2 Hz,5-CH₃), 1.10 (3H, s, 4a-CH₃), 1.57 (1H, m, OCOC₃ H₅), 1.87 (3H, d, J=1.9Hz, 3-CH₃), 2.07 (1H, dq, J=7.2, 2.8 Hz, 5-H), 2.14 (1H, br d, J=15.9Hz, 4-H), 2.80 (1H, d, J=15.9 Hz, 4-H), 3.09 (3H, s, N--CH₃), 3.49 (3H,s, O--CH₃), 3.60 (1H, dd, J=4.7, 1.3 Hz, 7-H), 5.07 (1H, m, 6-H), 5.73(1H, s, 9-H), 5.75 (1H, d, J=4.7 Hz, 8-H); MS (EI) m/z 357 (M)⁺ ; [α]²⁰_(D) -196° (c 1.0, MeOH).

Example 28

(4aR, 5R, 6R, 7R)-6-Benzoyloxy-7-methoxy-4a, 5, 6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (28 mg=0.10 mmol) prepared in Example 24 was dissolved inpyridine (1 ml), benzoyl chloride (34 μl=0.29 mmol) was added to thesolution, and the mixture was stirred at room temperature for 20 hr.Methylene chloride (20 ml) was added to the reaction mixture, and themixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (20 ml×2) and saturated saline (20 ml). The solvent was removedunder reduced pressure. The organic phase was dried over sodium sulfate,and the solvent was removed under reduced pressure. The residue waspurified by preparative TLC to give the title compound (33 mg, 87%).

¹ H NMR (CDCl₃) δ 1.17 (3H, d, J=7.2 Hz, 5-CH₃), 1.25 (3H, s, 4a-CH₃),1.89 (3H, d, J=1.9 Hz, 3-CH₃), 2.20 (1H, br d, J=15.9 Hz, 4-H), 2.21(1H, dq, J=7.2, 2.8 Hz, 5-H), 2.85 (1H, d, J=15.9 Hz, 4-H), 3.11 (3H, s,N--CH₃), 3.57 (3H, s, O--CH₃), 3.75 (1H, dd, J=4.7, 1.3 Hz, 7-H), 5.36(1H, m, 6-H), 5.76 (1H, s, 9-H), 5.79 (1H, d, J=4.7 Hz, 8-H), 7.40-8.00(5H, m, OCOC₆ H₅ ); MS (FAB) m/z 394 (M+H)⁺ ; [α]²⁰ _(D) +12° (c 1.0,MeOH)

Example 29

(4aR,5R,6R,7R)-7-Methoxy-6-(4-methoxy)benzoyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (28 mg=0.10 mmol) prepared in Example 24 was dissolved inpyridine (1 ml), 4-methoxybenzoyl chloride (50 mg=0.29 mmol) was addedto the solution, and the mixture was stirred at room temperature for 22hr. Methylene chloride (20 ml) was added to the reaction mixture, andthe mixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (20 ml×2) and saturated saline (20 ml). The solvent was removedunder reduced pressure. The organic phase was dried over sodium sulfate,and the solvent was removed under reduced pressure. The residue waspurified by preparative TLC to give the title compound (35 mg, 85%).

¹ H NMR (CDCl₃) δ 1.15 (3H, d, J=7.2 Hz, 5-CH₃), 1.24 (3H, s, 4a-CH₃),1.88 (3H, d, J=1.9 Hz, 3-CH₃), 2.19 (1H, br d, J=15.9 Hz, 4-H), 2.19(1H, dq, J=7.2, 2.8 Hz, 5-H), 2.84 (1H, d, J=15.9 Hz, 4-H), 3.11 (3H, s,N--CH₃), 3.57 (3H, s, O--CH₃), 3.74 (1H, dd, J=4.7, 1.3 Hz, 7-H), 3.84(3H, s, OCOC₆ H₄ --OCH₃ ), 5.33 (1H, m, 6-H), 5.76 (1H, s, 9-H), 5.78(1H, d, J=4.7 Hz, 8-H), 6.91 (2H, d, J=8.7 Hz, OCOC₆ H₄ --OCH₃), 7.93(2H, d, J=8.7 Hz, OCOC₆ H₄ --OCH₃); MS (FAB) m/z 424 (M+H)⁺ ; [α]²⁰ _(D)+95° (c 1.0, MeOH).

Example 30

(4aR,5R,6R,7R)-7-Methoxy-6-(4-nitro)benzoyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (28 mg=0.10 mmol) prepared in Example 24 was dissolved inpyridine (1 ml), 4-nitrobenzoyl chloride (54 mg=0.29 mmol) was added tothe solution, and the mixture was stirred at room temperature for 18 hr.Methylene chloride (20 ml) was added to the reaction mixture, and themixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (20 ml×2) and saturated saline (20 ml). The solvent was removedunder reduced pressure, and the organic phase was dried over sodiumsulfate. The solvent was removed under reduced pressure, and the residuewas purified by preparative TLC to give the title compound (37 mg, 87%).

¹ H NMR (CDCl₃) δ 1.17 (3H, d, J=7.2 Hz, 5-CH₃), 1.23 (3H, s, 4a-CH₃),1.89 (3H, d, J=1.9 Hz, 3-CH₃), 2.21 (1H, br d, J=15.9 Hz, 4-H), 2.25(1H, dq, J=7.2, 2.8 Hz, 5-H), 2.85 (1H, d, J=15.9 Hz, 4-H), 3.12 (3H, s,N--CH₃), 3.57 (3H, s, O--CH₃), 3.76 (1H, dd, J=4.7, 1.3 Hz, 7-H), 5.39(1H, m, 6-H), 5.76 (1H, s, 9-H), 5.79 (1H, d, J=4.7 Hz, 8-H), 8.14 (2H,d, J=9.0 Hz, OCOC₆ H₄ --NO₂), 8.29 (2H, d, J=9.0 Hz, OCOC₆ H₄ --NO₂); MS(FAB) m/z 439 (M+H)⁺ ; [α]²⁰ _(D) +80° (c 1.0, MeOH).

Example 31

(4aR,5R,6R,7R)-7-Methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethyl-6-(2-thiophenecarbonyloxy)benz[f]indol-2(4H)-one

The compound (17 mg=0.06 mmol) prepared in Example 24 was dissolved inpyridine (1 ml), 2-thenoyl chloride (19 μl=0.18 mmol) was added thereto,and the mixture was stirred at room temperature for 18 hr. Methylenechloride (20 ml) was added to the reaction mixture, and the mixture waswashed with a saturated aqueous sodium hydrogencarbonate solution (20ml×2) and saturated saline (20 ml). The solvent was removed underreduced pressure. The organic phase was dried over sodium sulfate, andthe solvent was removed under reduced pressure. The residue was purifiedby preparative TLC to give the title compound (21 mg, 89%).

¹ H NMR (CDCl₃) δ 1.16 (3H, d, J=7.2 Hz, 5-CH₃), 1.22 (3H, 5, 4a-CH₃),1.88 (3H, d, J=1.9 Hz, 3-CH₃), 2.17 (1H, dq, J=7.2, 2.8 Hz, 5-H), 2.18(1H, br d, J=15.9 Hz, 4-H), 2.83 (1H, d, J=15.9 Hz, 4-H), 3.10 (3H, s,N--CH₃), 3.55 (3H, s, O--CH₃), 3.76 (1H, br d, J=4.8 Hz, 7-H), 5.27 (1H,m, 6-H), 5.75 (1H, s, 9-H), 5.77 (1H, d, J=4.8 Hz, 8-H), 7.10 (1H, dd,J=4.9, 3.8 Hz, OCOC₄ H₃ S), 7.55 (1H, dd, J=4.9, 1.3 Hz, OCOC₄ H₃ S),7.77 (1H, dd, J=3.8, 1.3 Hz, OCOC₄ H₃ S); MS (EI)m/z 399 (M)⁺ ; [α]¹⁸_(D) +36° (c 1.0, MeOH); mp 148-153° C.

Example 32

(4aR,5R,6R,7R)-6-(2-Furancarbonyloxy)-7-methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (12 mg=0.04 mmol) prepared in Example 24 was dissolved inpyridine (1 ml), 2-furoyl chloride (11 μl=0.12 mmol) was added to thesolution, and the mixture was stirred at room temperature for 6 hr.Methylene chloride (20 ml) was added to the reaction solution, and themixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (20 ml×2) and saturated saline (20 ml). The solvent was removedunder reduced pressure. The organic phase was dried over sodium sulfate,and the solvent was removed under reduced pressure. The residue waspurified by preparative TLC to give the title compound (12 mg, 75%).

¹ H NMR (CDCl₃) δ 1.15 (3H, d, J=7.2 Hz, 5-CH₃), 1. 21 (3H, s, 4a-CH₃),1.88 (3H, d, J=1.9 Hz, 3-CH₃), 2.17 (1H, dq, J=7.2, 2.8 Hz, 5-H), 2.17(1H, br d, J=15.9 Hz, 4-H), 2.83 (1H, d, J=15.9 Hz, 4-H), 3.10 (3H, s,N--CH₃), 3.54 (3H, s, O--CH₃), 3.73 (1H, dd, J=4.8, 1.3 Hz, 7-H), 5.30(1H, m, 6-H), 5.75 (1H, s, 9-H), 5.77 (1H, d, J=4.8 Hz, 8-H), 6.49 (1H,dd, J=3.5, 1.7 Hz, OCOC₄ H₃ O), 7.10 (1H, dd, J=3.5, 0.8 Hz, OCOC₄ H₃O), 7.57 (1H, dd, J=1.7, 0.8 Hz, OCOC₄ H₃ O); MS (FAB) m/z 384 (M+H)⁺ ;[α]¹⁸ _(D) 0° (c 1.0, MeOH); mp 155-158° C.

Example 33

(4aR,5R,6R,7R)-7-Methoxy-6-(3-pyridinecarbonyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 3 was repeated, except that the compound (30mg=0.10 mmol) prepared in Example 24 was dissolved in pyridine (0.5 ml),nicotinoyl chloride hydrochloride (56 mg 0.31 mmol) was added to thesolution, and the mixture was stirred at 5° C. for 20 hr. Thus, thetitle compound (22 mg, 54%) was prepared.

¹ H NMR (CDCl₃) δ 1.17 (3H, d, J=7.1 Hz, 5-CH₃), 1.23 (3H, s, 4a-CH₃),1.88 (3H, d, J=1.9 Hz, 3-CH₃), 2.20 (1H, br d, J=15.9 Hz, 4-H), 2.23(1H, dq, J=7.1, 2.8 Hz, 5-H), 2.85 (1H, d, J=15.9 Hz, 4-H), 3.11 (3H, s,N--CH₃), 3.57 (3H, s, OCH₃), 3.76 (1H, dd, J=4.7, 1.4 Hz, 7-H), 5.38(1H, m, 6-H), 5.75 (1H, s, 9-H), 5.78 (1H, d, J=4.7 Hz, 8-H),7.40-8.76(4H, m, OCOC₅ H₄ N); MS (EI) m/z 363 (M)⁺ ; [α]²⁰ _(D) -7° (c1.0, MeOH).

Example 34

(4aR,5R,6R,7R)-6,7-Dimethoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (20 mg=0.07 mmol) prepared in Example 24 was dissolved inDMF (400 μl), and 60% sodium hydride (NaH) (14 mg=0.35 mmol) as an oilwas gradually added to the solution under ice cooling. After foamingsubsided, methyl iodide (22 μl=0.35 mmol) was added thereto, and themixture was stirred at room temperature for 2 hr. Methylene chloride (20ml) was added to the reaction mixture, and the mixture was washed withwater (20 ml) and saturated saline (20 ml). The solvent was removedunder reduced pressure, the organic phase was dried over sodium sulfate,and the solvent was removed under reduced pressure. The residue waspurified by preparative TLC to give the title compound (13 mg, 62%).

¹ H NMR (CDCl₃) δ 1.05 (3H, s, 4a-CH₃), 1.16 (3H, d, J=7.1 Hz, 5-CH₃),1.85 (3H, d, J=2.0 Hz, 3-CH₃), 1.89 (1H, dq, J=7.1, 2.8 Hz, 5-H), 2.09(1H, br d, J=15.9 Hz, 4-H), 2.77 (1H, d, J=15.9 Hz, 4-H), 3.08 (3H, s,N--CH₃), 3.28 (1H, m, 6-H), 3.40 (3H, s, O--CH₃), 3.43 (3H, s, O--CH₃),3.74 (1H, dd, J=4.8, 1.4 Hz, 7-H), 5.72 (1H, s, 9-H), 5.81 (1H, d, J=4.8Hz, 8-H); MS (EI) m/z 303 (M)⁺ ; [α]¹⁸ _(D) -340° (c 1.0, MeOH).

Example 35

(4aR,5R,6R,7R)-6-Ethoxy-7-methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (25 mg=0.09 mmol) prepared in Example 24 was dissolved indimethylformamide (500 μl), and 60% sodium hydride (NaH) as an oil (18mg=0.45 mmol) was gradually added to the solution under ice cooling.After foaming subsided, ethyl iodide (35 μl=0.45 mmol) was addedthereto, and the mixture was stirred at room temperature for 2.5 hr.Methylene chloride (20 ml) was added to the reaction mixture, and themixture was washed with water (20 ml) and saturated saline (20 ml). Thesolvent was removed under reduced pressure. The organic phase was driedover sodium sulfate, and the solvent was removed under reduced pressure.The residue was purified by preparative TLC to give the title compound(10 mg, 36%).

¹ H NMR (CDCl₃) δ 1.06 (3H, s, 4a-CH₃), 1.14 (3H, d, J=7.1 Hz, 5-CH₃),1.17 (3H, t, J=7.0 Hz, OCH₂ CH₃ ), 1.85 (3H, d, J=2.0 Hz, 3-CH₃), 1.87(1H, dq, J=7.1, 2.8 Hz, 5-H), 2.09 (1H, br d, J=15.9 Hz, 4-H), 2.77 (1H,d, J=15.9 Hz, 4-H), 3.08 (3H, s, N--CH₃), 3.38 (1H, m, 6-H), 3.42 (1H,dq, J=7.0, 2.3 Hz, OCH₂ CH₃), 3.42 (3H, s, O--CH₃), 3.66 (1H, dq, J=7.0,2.3 Hz, OCH₂ CH₃), 3.70 (1H, dd, J=4.8, 1.4 Hz, 7-H), 5.72 (1H, s, 9-H),5.81 (1H, d, J=4.8 Hz, 8-H); MS (EI) m/z 317 (M)⁺ ; [α]¹⁸ _(D) -300° (c1.0, MeOH).

Example 36

(4aR,5R,6R,7R)-7-Methoxy-6-propoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (50 mg=0.17 mmol) prepared in Example 24 was dissolved indimethylformamide (500 μl), and 60% sodium hydride (NaH) as an oil (35mg 0.87 mmol) was gradually added to the solution under ice cooling.After foaming subsided, n-propyl iodide (84 μl=0.87 mmol) was addedthereto, and the mixture was stirred at room temperature for 4 hr.Methylene chloride (20 ml) was added to the reaction mixture, themixture was washed with water (20 ml) and saturated saline (20 ml), andthe solvent was removed under reduced pressure. The organic phase wasdried over sodium sulfate, and the solvent was removed under reducedpressure. The residue was purified by preparative TLC to give the titlecompound (14 mg, 24%).

¹ H NMR (CDCl₃) δ 0.91 (3H, t, J=6.4 Hz, OCH₂ CH₂ CH₃ ), 1.07 (3H, s,4a-CH₃), 1.14 (3H, d, J=7.1 Hz, 5-CH₃), 1.55 (2H, seq, J=6.4 Hz, OCH₂CH₂ CH₃), 1.85 (3H, d, J=2.0 Hz, 3-CH₃), 1.87 (1H, dq, J=7.1, 2.8 Hz,5-H), 2.09 (1H, br d, J=15.9 Hz, 4-H), 2.77 (1H, d, J=15.9 Hz, 4-H),3.08 (3H, s, N--CH₃), 3.30 (1H, dt,J=9.0, 6.4 Hz, OCH₂ CH₂ CH₃), 3.37(1H, m, 6-H), 3.42 (3H, s, OCH₃), 3.57 (1H, dt, J=9.0, 6.4 Hz, OCH₂ CH₂CH₃), 3.70 (1H, dd, J=4.8, 1.4 Hz, 7-H), 5.72 (1H, s, 9-H), 5.80 (1H, d,J=4.8 Hz, 8-H); MS (EI) m/z 331 (M)⁺ ; [α]¹⁸ _(D) -309° (c 1.0, MeOH).

Example 37

(4aR,5R,6R,7R)-6-Butoxy-7-methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 34 was repeated, except that the compound (10mg=0.03 mmol) prepared in Example 24 was dissolved in DMF (1 ml), 60%sodium hydride (4 mg=0.10 mmol) as an oil and butyl iodide (24 μl=0.21mmol) were added to the solution, and the mixture was stirred at roomtemperature for 3 hr. Thus, the title compound (4 mg, 31%) was prepared.

¹ H NMR (CDCl₃) δ 0.91 (3H, t, J=7.3 Hz, OCH₂ CH₂ CH₂ CH₃), 1.08 (3H, s,4a-CH₃), 1.16 (3H, d, J=7.2 Hz, 5-CH₃), 1.38 (2H, m, OCH₂ CH₂ CH₂ CH₃),1.54 (2H, m, OCH₂ CH₂ CH₂ CH₃), 1.87 (3H, d, J=2.0 Hz, 3-CH₃), 1.89 (1H,dq, J=7.2, 2.7 Hz, 5-H), 2.11 (1H, br d, J=15,9 Hz, 4-H), 2.78 (1H, d,J=15.9 Hz, 4-H), 3.10 (3H, s, N--CH₃), 3.36 (1H, dt, J=9.0, 6.3 Hz, OCH₂CH₂ CH₂ CH₃), 3.38 (1H, m, 6-H), 3.44 (3H, s, OCH₃), 3.62 (1H, dt,J=9.0, 6.3 Hz, OCH₂ CH₂ CH₂ CH₃), 3.72 (1H, br d, J=4.4 Hz, 7-H), 5.74(1H, s, 9-H), 5.82 (1H, d, J=4.4 Hz, 8-H); MS (TSP) m/z 346 (M+H)⁺.

Example 38

(4aR,5R,6R,7R)-7-Methoxy-6-(3-methylbutoxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 34 was repeated, except that the compound (30mg=0.10 mmol) prepared in Example 24 was dissolved in DMF (0.2 ml), 60%sodium hydride as an oil (13 mg=0.31 mmol) and isoamyl iodide (82μl=0.62 mmol) were added to the solution, and the mixture was stirred at50° C. for 3 hr. Thus, the title compound (7 mg, 19%) was prepared.

¹ H NMR (CDCl₃) δ 0.88 (3H, d, J=6.7 Hz, OCH₂ CH₂ CH(CH₃)₂), 0.88 (3H,d, J=6.7 Hz, OCH₂ CH₂ CH(CH₃)₂), 1.06 (3H, s, 4a-CH₃), 1.14 (3H, d,J=7.1 Hz,5-CH₃), 1.43 (2H, m, OCH₂ CH₂ CH(CH₃)₂), 1.70 (1H, m, OCH₂ CH₂CH(CH₃)₂), 1.86 (3H, d, J=1.9 Hz, 3-CH₃), 1.87 (1H, dq, J=7.1, 2.8 Hz,5-H), 2.09 (1H, br d, J=15.9 Hz, 4-H), 2.77 (1H, d, J=15.9 Hz, 4-H),3.08 (3H, s, N--CH₃), 3.36 (1H, m, 6-H), 3.36 (1H, dt, J=9.1, 6.3 Hz,OCH₂ CH₂ CH(CH₃)₂), 3.43 (3H, s, OCH₃), 3.63 (1H, dt, J=9.1, 6.3 Hz,OCH₂ CH₂ CH(CH₃)₂), 3.71 (1H, dd, J=4.7, 1.4 Hz, 7-H), 5.72 (1H, s,9-H), 5.81 (1H, d, J=4.7 Hz, 8-H); MS (EI) m/z 359 (M)⁺ ; [α]²⁰ _(D)-157° (c 1.0, MeOH).

Example 39

(4aR,5R,6R,7R)-7-Methoxy-6-[(2S)-2-methylbutoxy]-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 34 was repeated, except that the compound (92mg=0.32 mmol) prepared in Example 24 was dissolved in DMF (0.5 ml), 60%sodium hydride as an oil (39 mg=0.98 mmol) and(S)-(+)-1-iodo-2-methylbutane (0.25 ml=1.91 mmol) were added to thesolution, and the mixture was stirred at 50° C. for 3 hr. Thus, thetitle compound (1 mg, 1%) was prepared.

¹ H NMR (CDCl₃) δ 0.87 (3H, t, J=7.5 Hz, OCH₂ CH(CH₃)CH₂ CH₃), 0.88 (3H,d, J=7.4 Hz, OCH₂ CH(CH₃)CH₂ CH₃), 1.07 (3H, s, 4a-CH₃), 1.15 (3H, d,J=7.1 Hz, 5-CH₃), 1.31 (3H, m, OCH₂ CH(CH₃)CH₂ CH₃), 1.86 (3H, d, J=1.9Hz, 3-CH₃), 1.88 (1H, dq, J=7.1, 2.8 Hz, 5-H), 2.09 (1H, br d, J=15.9Hz, 4-H), 2.77 (1H, d, J=15.9 Hz, 4-H), 3.09 (3H, s, N--CH₃), 3.20 (1H,dd, J=8.7, 5.6 Hz, OCH₂ CH(CH₃)CH₂ CH₃), 3.35 (1H, m, 6-H), 3.42 (1H,dd, J=8.7, 5.6 Hz, OCH₂ CH(CH₃),CH₂ CH₃), 3.43 (3H, s, OCH₃), 3.70 (1H,dd, J=4.7, 1.4 Hz, 7-H), 5.73 (1H, s, 9-H), 5.80 (1H, d, J=4.7 Hz, 8-H);MS (EI) m/z 359 (M)⁺ ; [α]²⁰ _(D) -35° (c 1.0, MeOH).

Example 40

(4aR,5R,6R,7R)-6-Cyclopropylmethoxy-7-methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 34 was repeated, except that the compound (52mg=0.18 mmol) prepared in Example 24 was dissolved in DMF (0.5 ml), 60%sodium hydride as an oil (22 mg=0.54 mmol) and (bromomethyl)cyclopropane(0.10 ml=1.08 mmol) were added to the solution, and the mixture wasstirred at 50° C. for 3 hr. Thus, the title compound (25 mg, 40%) wasprepared.

¹ H NMR (CDCl₃) δ 0.20-0.48 (4H, m, OCH₂ C₃ H₅), 1.02 (1H, m, OCH₂ C₃H₅), 1.09 (3H, s, 4a-CH₃), 1.16 (3H, d, J=7.1 Hz, 5-CH₃), 1.86 (3H, d,J=1.9 Hz, 3-CH₃), 1.88 (1H, dq, J=7.1, 2.8 Hz, 5-H), 2.10 (1H, br d,J=15.9 Hz, 4-H), 2.78 (1H, d, J=15.9 Hz, 4-H), 3.09 (3H, s, N--CH₃),3.27 (1H, dd, J=10.1, 6.4 Hz, OCH₂ C₃ H₅), 3.42 (3H, s, OCH₃), 3.43 (1H,m, 6-H), 3.46 (1H, dd, J=10.1, 6.4 Hz, OCH₂ C₃ H₅), 3.71 (1H, dd, J=4.7,1.4 Hz, 7-H), 5.73 (1H, s, 9-H), 5.82 (1H, d, J=4.7 Hz, 8-H); MS (EI)m/z 343 (M)⁺ ; [α]²⁰ _(D) -264° (c 1.0, MeOH).

Example 41

(4aR,5R,6R,7R)-7-Methoxy-6-(2-propenyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (28 mg=0.10 mmol) prepared in Example 24 was dissolved indimethylformamide (500 μl), 60% sodium hydride (NaH) (20 mg=0.49 mmol)as an oil was gradually added to the solution under ice cooling. Afterfoaming subsided, allyl iodide (45 μl=0.49 mmol) was added thereto, andthe mixture was stirred at room temperature for 1.5 hr. Methylenechloride (20 ml) was added to the reaction mixture, the mixture waswashed with water (20 ml) and saturated saline (20 ml), and the solventwas removed under reduced pressure. The organic phase was dried oversodium sulfate, and the solvent was removed under reduced pressure. Theresidue was purified by preparative TLC to give the title compound (22mg, 69%).

¹ H NMR (CDCl₃) δ 1.08 (3H, s, 4a-CH₃), 1.15 (3H, d, J=7.1 Hz, 5-CH₃),1.85 (3H, d, J=2.0 Hz, 3-CH₃), 1.90 (1H, dq, J=7.1, 2.8 Hz, 5-H), 2.10(1H, br d, J=15.9 Hz, 4-H), 2.78 (1H, d, J=15.9 Hz, 4-H), 3.08 (3H, s,N--CH₃), 3.41 (3H, s, O--CH₃), 3.46 (1H, m, 6-H), 3.72 (1H, dd, J=4.8,1.4 Hz, 7-H), 3.94 (1H, ddt, J=13.1, 5.6, 1.5 Hz, OCH₂ CH═CH₂), 4.15(1H, ddt, J=13.1, 5.6, 1.5 Hz, OCH₂ CH═CH₂), 5.20 (2H, m, OCH₂ CH═CH₂),5.72 (1H, s, 9-H), 5.80 (1H, d, J=4.8 Hz, 8-H), 5.89 (1H, m, OCH₂CH═CH₂); MS (EI)m/z 329 (M)⁺ ; [α]¹⁸ _(D) -272° (c 1.0, MeOH).

Example 42

(4aR,5R,6R,7R)-7-Methoxy-6-[(E)-3-phenyl-2-propenyloxy]-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 34 was repeated, except that the compound (10mg=0.03 mmol) prepared in Example 24 was dissolved in DMF(1 ml), 60%sodium hydride (4 mg=0.10 mmol) as an oil and cinnamyl bromide (31μl=0.21 mmol), and the mixture was stirred at room temperature for 4 hr.Thus, the title compound (4 mg, 29%) was prepared.

¹ H NMR (CDCl₃) δ 1.13 (3H, s, 4a-CH₃), 1.19 (3H, d, J=7.1 Hz, 5-CH₃),1.88 (3H, d, J=1.9 Hz, 3-CH₃), 1.94 (1H, dq, J=7.1, 2.7 Hz, 5-H), 2.12(1H, br d, J=16.0 Hz, 4-H), 2.80 (1H, d, J=16.0 Hz, 4-H), 3.10 (3H, s,N--CH₃), 3.44 (3H, s, OCH₃), 3.55 (1H, m, 6-H), 3.78 (1H, dd, J=4.8, 1.2Hz, 7-H), 4.14 (1H, dd, J=13.1, 5.8 Hz, OCH₂ CHCHC₆ H₅), 4.32 (1H, dd,J=13.1, 5.8 Hz, OCH₂ CHCHC₆ H₅), 5.75 (1H, s, 9-H), 5.84 (1H, d, J=4.8Hz, 8-H), 6.27 (1H, dt, J=15.9, 5.8 Hz, OCH₂ CHCHC₆ H₅), 6.60 (1H, d,J=15.9 Hz, OCH₂ CHCHC₆ H₅), 7.22-7.39 (5H, m, OCH₂ CHCHC₆ H₅); MS (TSP)m/z 406 (M+H)⁺ ;

Example 43

(4aR,5R,6R,7R)-6-Benzyloxy-7-methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (35 mg=0.12 mmol) prepared in Example 24 was dissolved indimethylformamide (500 μl), 60% sodium hydride (NaH) (25 mg=0.60 mmol)as an oil was gradually added to the solution under ice cooling. Afterfoaming subsided, benzyl bromide (72 μl=0.60 mmol) was added thereto,and the mixture was stirred at room temperature for 1 hr. Methylenechloride (20 ml) was thereto, and the mixture was washed with water (20ml) and saturated saline (20 ml), and the solvent was removed underreduced pressure. The organic phase was dried over sodium sulfate, andthe solvent was removed under reduced pressure. The residue was purifiedby preparative TLC to give the title compound (32 mg, 70%).

¹ H NMR (CDCl₃) δ 1.13 (3H, s, 4a-CH₃), 1.14 (3H, d, J=7.1 Hz, 5-CH₃),1.86 (3H, d, J=2.0 Hz, 3-CH₃), 1.92 (1H, dq, J=7.1, 2.8 Hz, 5-H), 2.11(1H, br d, J=15.9 Hz, 4-H), 2.78 (1H, d, J=15.9 Hz, 4-H), 3.09 (3H, s,N--CH₃), 3.40 (3H, s, O--CH₃), 3.55 (1H, m, 6-H), 3.78 (1H, dd, J=4.8,1.4 Hz, 7-H), 4.51 (1H, d, J=12.0 Hz, OCH₂ C₆ H₅), 4.69 (1H, d, J=12.0Hz, OCH₂ C₆ H₅), 5.72 (1H, s, 9-H), 5.80 (1H, d, J=4.8 Hz, 8-H),7.25-7.37 (5H, m, OCH₂ C₆ H₅ ); MS (EI)m/z 379 (M)⁺ ; [α]¹⁸ _(D) -198°(c 1.0, MeOH).

Example 44

(4aR,5R,6R,7R)-7-Methoxy-6-(4-methoxybenzyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 34 was repeated, except that the compound (10mg=0.03 mmol) prepared in Example 24 was dissolved in DMF(1 ml), 60%sodium hydride (4 mg=0.10 mmol) as an oil and 4-methoxybenzyl chloride(28 μl=0.21 mmol) were added to the solution, and the mixture wasstirred at room temperature for 5 hr. Thus, title compound (2 mg, 14%)was prepared.

¹ H NMR (CDCl₃) δ 1.11 (3H, s, 4a-CH₃), 1.13 (3H, d, J=7.1 Hz, 5-CH₃),1.87 (3H, d, J=1.7 Hz, 3-CH₃), 1.92 (1H, dq, J=7.1, 2.7 Hz, 5-H), 2.11(1H, br d, J=16.0 Hz, 4-H), 2.79 (1H, d, J=16.0 Hz, 4-H), 3.10 (3H, s,N--CH₃), 3.41 (3H, s, OCH₃), 3.54 (1H, m, 6-H), 3.78 (1H, br d, J=5.0Hz, 7-H), 3.81 (3H,s, OCH₂ C₆ H₄ --OCH₃), 4.45 (1H, d, J=11.5 Hz, OCH₂C₆ H₄ --OCH₃), 4.63 (1H, d, J=11.5 Hz, OCH₂ C₆ H₄ --OCH₃), 5.74 (1H, s,9-H), 5.82 (1H, d, J=5.0 Hz, 8-H), 6.87 (2H, d, J=8.6 Hz, OCH₂ C₆ H₄--OCH₃), 7.26 (2H, d, J=8.6 Hz, OCH₂ C₆ H₄ --OCH₃); MS (TSP) m/z 410(M+H)⁺.

Example 45

(4aR,5R,6R,7R)-6-(2,2-Dihydroxyethoxy)-7-methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (50 mg=0.15 mmol) prepared in Example 41 was dissolved in asolution of 1,4-dioxane (0.5 ml) in water (0.4 ml), a 4% aqueous osmiumtetraoxide solution (96 μl=0.02 mmol) and sodium periodate (65 mg=0.30mmol), and the mixture was stirred at room temperature for 30 min.Methylene chloride was added thereto, the mixture was washed with water,and the organic phase was dried over sodium sulfate. The solvent wasremoved under reduced pressure, and the residue was purified bypreparative TLC to give the title compound (40 mg, 75%).

¹ H NMR (CDCl₃) δ 1.01 (3H, s, 4a-CH₃), 1.14 (3H, d, J=7.1 Hz, 5-CH₃),1.83 (3H, d, J=1.9 Hz, 3-CH₃), 1.90 (1H, dq, J=7.1, 2.8 Hz, 5-H), 2.08(1H, br d, J=15.9 Hz, 4-H), 2.74 (1H, d, J=15.9 Hz, 4-H), 3.06 (3H, s,N--CH₃) 3.40 (3H, s, OCH₃), 3.42-3.75 (4H, m, 7-H, OCH₂ CH(OH)₂), 3.43(1H, m, 6-H), 5.71 (1H, s, 9-H), 5.78 (1H, d, J=4.7 Hz, 8-H); MS (EI)m/z 349 (M)⁺ ; [α]²⁰ _(D) -390° (c 1.0, MeOH).

Example 46

(4aR,5R,6R,7R)-6-(2-Hydroxyethoxy)-7-methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (40 mg=0.12 mmol) prepared in Example 45 was dissolved inmethanol (0.8 ml), sodium borohydride (9 mg=0.24 mmol) was added to thesolution, and the mixture was stirred at room temperature for 5 min.Methylene chloride was added to the reaction mixture, the mixture waswashed with water, and the organic phase was dried over sodium sulfate.The solvent was removed under reduced pressure, and the residue waspurified by preparative TLC to give the title compound (5 mg, 12%).

¹ H NMR (CDCl₃) δ 1.07 (3H, s, 4a-CH₃), 1.18 (3H, d, J=7.1 Hz, 5-CH₃),1.86 (3H, d, J=1.9 Hz, 3-CH₃), 1.94 (1H, dq, J=7.1, 2.8 Hz, 5-H), 2.11(1H, br d, J=15.9 Hz, 4-H), 2.78 (1H, d, J=15.9 Hz, 4-H), 3.09 (3H, s,N--CH₃), 3.43 (3H, s, OCH₃), 3.50-3.80 (5H, m, 7-H, OCH₂ CH₂ OH), 3.47(1H, m, 6-H), 5.73 (1H, s, 9-H), 5.81 (1H, d, J=4.7 Hz, 8-H); MS (EI)m/z 333 (M)⁺ ; [α]²⁰ _(D) -72° (c 0.4, MeOH).

Example 47

(4aR,5R,6R,7R)-6-(Imidazol-1-ylcarbonyloxy)-7-methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 5 was repeated, except that the compound (450mg=1.56 mmol) prepared in Example 24 was dissolved in methylene chloride(9 ml), 1,1-carbonyldiimidazole (532 mg=3.28 mmol) was added to thesolution, and the mixture was stirred at room temperature for 5 hr.Thus, the title compound (486 mg, 81%) was prepared.

¹ H NMR (CDCl₃) δ 1.19 (3H, s, 4a-CH₃), 1.22 (3H, d, J=7.3 Hz, 5-CH₃),1.91 (3H, d, J=1.9 Hz, 3-CH₃), 2.22 (1H, br d, J=16.0 Hz, 4-H), 2.26(1H, dq, J=7.3, 2.8 Hz, 5-H), 2.86 (1H, d, J=16.0 Hz, 4-H), 3.13 (3H, s,N--CH₃), 3.57 (3H, s, OCH₃), 3.83 (1H, dd, J=4.7, 1.2 Hz, 7-H), 5.28(1H, m, 6-H), 5.77 (1H, s, 9-H), 5.79 (1H, d, J=4.7 Hz, 8-H), 7.10 (1H,br s, OCOC₃ N₂), 7.39 (1H, br s, OCOC₃ N₂),8.11 (1H, br s, OCOC₃ N₂); MS(EI) m/z 383 (M)⁺.

Example 48

(4aR,5R,6R,7R)-6-Carbamoyloxy-7-methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (50 mg=0.13 mmol) prepared in Example 47 was dissolved inmethylene chloride (2 ml), methyl triflate (14 μl=0.12 mmol) was addedto the solution, and the mixture was stirred at 10° C. for 30 min. Anexcess of ammonia was added to the reaction mixture, and the mixture wasstirred at room temperature for 30 min. The solvent was removed underreduced pressure, and the residue was purified by column chromatographyon silica gel to give the title compound (30 mg, 70%).

¹ H NMR (CDCl₃) δ 1.03 (3H, s, 4a-CH₃), 1.14 (3H, d, J=7.2 Hz, 5-CH₃),1.87 (3H, d, J=1.9 Hz, 3-CH₃), 2.07 (1H, dq, J=7.2, 2.7 Hz, 5-H), 2.14(1H, br d, J=15.8 Hz, 4-H), 2.80 (1H, d, J=15.8 Hz, 4-H), 3.09 (3H, s,N--CH₃), 3.52 (3H, s, OCH₃), 3.70 (1H, dd, J=4.8, 1.5 Hz, 7-H), 4.73(2H, m, OCONH₂), 4.99 (1H, m, 6-H), 5.73 (1H, s, 9-H), 5.78 (1H, d,J=4.8 Hz, 8-H); MS (FAB) m/z 333 (M+H)⁺.

Example 49

(4aR,5R,6R,7R)-7-Methoxy-6-methylcarbamoyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (58mg=0.15 mmol) prepared in Example 47 was dissolved in THF (0.4 ml), a 2M methylamine/THF solution (0.76 ml=1.52 mmol) was added to thesolution, and the mixture was stirred at room temperature for 3 hr,followed by purification by preparative TLC. Thus, the title compound(52 mg, 99%) was prepared.

¹ H NMR (CDCl₃) δ 0.97 (3H, s, 4a-CH₃), 1.10 (3H, d, J=7.1 Hz, 5-CH₃),1.84 (3H, br s, 3-CH₃), 2.03 (1H, dq, J=7.1, 2.6 Hz, 5-H), 2.11 (1H, brd, J=16.3 Hz, 4-H), 2.77 (1H, d, J=16.3 Hz, 4-H), 2.82 (3H, d, J=4.7 Hz,OCONHCH₃), 3.06 (3H, s, N--CH₃), 3.51 (3H, s, OCH₃), 3.67 (1H, br d,J=4.8 Hz, 7-H), 4.97 (1H, m, 6-H), 5.11 (1H, m, OCONHCH₃), 5.70 (1H, s,9-H), 5.75 (1H, d, J=4.8 Hz, 8-H); MS (FAB) m/z 347 (M+H)⁺.

Example 50

(4aR,5R,6R,7R)-6-Ethylcarbamoyloxy-7-methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (57mg=0.15 mmol) prepared in Example 47 was dissolved in THF (0.4 ml), a 2M ethylamine/THF solution (0.75 ml=1.50 mmol) was added to the solution,and the mixture was stirred at room temperature for 1.5 hr, followed bypurification by preparative TLC. Thus, the title compound (53 mg, 97%)was prepared.

¹ H NMR (CDCl₃) δ 1.02 (3H, s, 4a-CH₃), 1.12 (3H, d, J=7.1 Hz, 5-CH₃),1.16 (3H, t, J=6.9 Hz, OCONHCH₂ CH₃), 1.86 (3H, br s, 3-CH₃), 2.05 (1H,dq, J=7.1, 1.9 Hz, 5-H), 2.13 (1H, br d, J=16.0 Hz, 4-H), 2.79 (1H, d,J=16.0 Hz, 4-H), 3.08 (3H, s, N--CH₃), 3.25 (2H, br q, J=6.9 Hz,OCONHCH₂ CH₃), 3.52 (3H, s, OCH₃), 3.69 (1H, br d, J=4.7 Hz, 7-H), 4.49(1H, m, OCONHCH₂ CH₃), 4.97 (1H, m, 6-H), 5.72 (1H, s, 9-H), 5.76 (1H,d, J=4.7 Hz, 8-H); MS (FAB) m/z 361 (M+H)⁺.

Example 51

(4aR,5R,6R,7R)-7-Methoxy-6-propylcarbamoyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (30 mg=0.10 mmol) prepared in Example 24 was dissolved inDMF (0.6 ml), propyl isocyanate (0.19 ml=2.07 mmol) was added to thesolution in the presence of 4-dimethylaminopyridine (258 mg=2.11 mmol),and the mixture was stirred at 80° C. for 4.5 hr. Ethyl acetate wasadded to the reaction mixture, the mixture was washed with water, andthe organic phase was dried over sodium sulfate. The solvent was removedunder reduced pressure, and the residue was purified by preparative TLCto give the title compound (34 mg, 88%).

¹ H NMR (CDCl₃) δ 0.92 (3H, t, J=7.2 Hz, OCONHCH₂ CH₂ CH₃), 0.99 (3H, s,4a-CH₃), 1.11 (3H, d, J=6.8 Hz, 5-CH₃), 1.54 (2H, seq, J=7.2 Hz,OCONHCH₂ CH₂ CH₃), 1.85 (3H, br s, 3-CH₃), 2.04 (1H, dq, J=6.8, 1.9 Hz,5-H), 2.11 (1H, br d, J=16.3 Hz, 4-H), 2.77 (1H, d, J=16.3 Hz, 4-H),3.06 (3H, s, N--CH₃), 3.15 (2H, br dt, J=7.2 Hz, OCONHCH₂ CH₂ CH₃), 3.51(3H, s, OCH₃), 3.67 (1H, br d, J=4.9 Hz, 7-H), 4.97 (1H, m, 6-H), 5.08(1H, m, OCONHCH₂ CH₂ CH₃), 5.71 (1H, s, 9-H), 5.75 (1H, d, J=4.9 Hz,8-H); MS (EI) m/z 375 (M+H)⁺.

Example 52

(4aR,5R,6R,7R)-7-Methoxy-6-(1-methylethylcarbamoyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (30mg=0.08 mmol) prepared in Example 47 was dissolved in toluene (1 ml),isopropylamine (33 μl=0.39 mmol) was added to the solution, and themixture was stirred at 6° C. for 15 hr and then at 9° C. for 4 hr. Thus,the title compound (9 mg, 31%) was prepared.

¹ H NMR (CDCl₃) δ 1.07 (3H, s, 4a-CH₃), 1.13 (3H, d, J=7.2 Hz, 5-CH₃),1.15 (3H, d, J=6.1 Hz, OCONHCH(CH₃)₂), 1.17 (3H, d, J=6.1 Hz,OCONHCH(CH₃)₂), 1.88 (3H, d, J=1.8 Hz, 3-CH₃), 2.07 (1H, m, 5-H), 2.14(1H, br d, J=16.2 Hz, 4-H), 2.80 (1H, d, J=16.2 Hz, 4-H), 3.10 (3H, s,N--CH₃), 3.53 (3H, s, OCH₃), 3.69 (1H, dd, J=4.8, 1.4 Hz, 7-H), 3.82(1H, m, OCONHCH(CH₃)₂), 4.51 (1H, m, OCONHCH(CH₃)₂), 4.97 (1H, m, 6-H),5.74 (1H, s, 9-H), 5.77 (1H, d, J=4.8 Hz, 8-H); MS (TSP) m/z 375 (M+H)⁺.

Example 53

(4aR,5R,6R,7R)-7-Methoxy-6-(2-methylpropylcarbamoyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (30mg=0.08 mmol) prepared in Example 47 was dissolved in toluene (1 ml),isobutylamine (38 μl=0.38 mmol) was added to the solution, and themixture was stirred at room temperature for two days. Thus, the titlecompound (20 mg, 66%) was prepared.

¹ H NMR (CDCl₃) δ 0.92 (6H, d, J=6.8 Hz, OCONHCH₂ CH(CH₃)₂), 1.06 (3H,s, 4a-CH₃), 1.13 (3H, d, J=7.1 Hz, 5-CH₃), 1.78 (1H, m, OCONHCH₂CH(CH₃)₂), 1.87 (3H, br s, 3-CH₃), 2.06 (1H, m, 5-H), 2.14 (1H, br d,J=15.9 Hz, 4-H), 2.80 (1H, d, J=15.9 Hz, 4-H), 3.02 (2H, m, OCONHCH₂CH(CH₃)₂), 3.10 (3H, s, N--CH₃), 3.53 (3H, s, OCH₃), 3.68 (1H, br d,J=4.7 Hz, 7-H), 4.83 (1H, m, OCONHCH₂ CH(CH₃)₂), 4.99 (1H, m, 6-H), 5.73(1H, s, 9-H), 5.77 (1H, d, J=4.7 Hz, 8-H); MS (TSP) m/z 389 (M+H)⁺.

Example 54

(4aR,5R,6R,7R)-6-Hexylcarbamoyloxy-7-methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (30mg=0.08 mmol) prepared in Example 47 was dissolved in toluene (1 ml),hexylamine (0.10 ml=0.78 mmol) was added to the solution, and themixture was stirred at room temperature for 2 hr. Thus, the titlecompound (30 mg, 93%) was prepared.

¹ H NMR (CDCl₃) δ 0.88 (3H, m, OCONHCH₂ CH₂ (CH₂)₃ CH₃), 1.05 (3H, s,4a-CH₃), 1.13 (3H, d, J=7.1 Hz, 5-CH₃), 1.29 (6H, m, OCONHCH₂ CH₂ (CH₂)₃CH₃), 1.51 (2H, m, OCONHCH₂ CH₂ (CH₂)₃ CH₃), 1.87 (3H, d, J=1.7 Hz,3-CH₃), 2.07 (1H, m, 5-H), 2.14 (1H, br d, J=15.9 Hz, 4-H), 2.80 (1H, d,J=15.9 Hz, 4-H), 3.10 (3H, s, N--CH₃), 3.19 (2H, m, OCONHCH₂ CH₂ (CH₂)₃CH₃), 3.53 (3H, s, OCH₃), 3.69 (1H, br d, J=4.7 Hz, 7-H), 4.79 (1H, m,OCONHCH₂ CH₂ (CH₂)₃ CH₃), 4.99 (1H, m, 6-H), 5.73 (1H, s, 9-H), 5.77(1H, d, J=4.7 Hz, 8-H); MS (TSP) m/z 417 (M+H)⁺.

Example 55

(4aR,5R,6R,7R)-6-Cyclopropylcarbamoyloxy-7-methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (20mg=0.05 mmol) prepared in Example 47 was dissolved in toluene (0.5 ml),cyclopropylamine (20 μl=0.29 mmol) was added to the solution, and themixture was stirred at room temperature for three days. Thus, the titlecompound (13 mg, 68%).

¹ H NMR (CDCl₃) δ 0.52-0.74 (4H, m, OCONHC₃ H₅), 1.00-1.22 (6H, m,4a-CH₃, 5-CH₃), 1.87 (3H, d, J=1.7 Hz, 3-CH₃), 2.10 (1H, m, 5-H), 2.14(1H, br d, J=15.9 Hz, 4-H), 2.61 (1H, m, OCONHC₃ H₅), 2.80 (1H, d,J=15.9 Hz, 4-H), 3.10 (3H, s, N--CH₃), 3.54 (3H, s, OCH₃), 3.71 (1H, brd, J=4.4 Hz, 7-H), 5.00 (2H, m, 6-H, OCONHC₃ H₅), 5.73 (1H, s, 9-H),5.76 (1H, d, J=4.4 Hz, 8-H); MS (TSP) m/z 373 (M+H)⁺.

Example 56

(4aR,5R,6R,7R)-6-Benzylcarbamoyloxy-7-methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (50mg=0.13 mmol) prepared in Example 47 was dissolved in toluene (1 ml),benzylamine (71 μl=0.65 mmol) was added to the solution, and the mixturewas stirred at 50° C. for 6 hr. Thus, the title compound (35 mg, 64%)was prepared.

¹ H NMR (CDCl₃) δ 1.03 (3H, s, 4a-CH₃), 1.14 (3H, d, J=7.1 Hz, 5-CH₃),1.86 (3H, d, J=1.7 Hz, 3-CH₃), 2.08 (1H, dq, J=7.1, 2.8 Hz, 5-H), 2.13(1H, br d, J=15.7 Hz, 4-H), 2.79 (1H, d, J=15.7 Hz, 4-H), 3.08 (3H, s,N--CH₃), 3.54 (3H, s, OCH₃), 3.72 (1H, br d, J=4.6 Hz, 7-H), 4.40 (2H,m, OCONHCH₂ C₆ H₅), 5.04 (1H, m, 6-H), 5.16 (1H, m, OCONHCH₂ C₆ H₅),5.72 (1H, s, 9-H), 5.77 (1H, d, J=4.6 Hz, 8-H), 7.27-7.35 (5H, m,OCONHCH₂ C₆ H₅); MS (TSP) m/z 423 (M+H)⁺.

Example 57

(4aR,5R,6R,7R)-7-Methoxy-6-phenylcarbamoyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 51 was repeated, except that the compound (27mg=0.09 mmol) prepared in Example 24 was dissolved in DMF (0.5 ml),phenyl isocyanate (0.10 ml=0.92 mmol) was added to the solution, and themixture was stirred at room temperature for 25 hr. Thus, the titlecompound (37 mg, 97%) was prepared.

¹ H NMR (CDCl₃) δ 0.96 (3H, s, 4a-CH₃), 1.17 (3H, d, J=7.2 Hz, 5-CH₃),1.87 (3H, d, J=1.9 Hz, 3-CH₃), 2.12 (1H, dq, J=7.2, 2.7 Hz, 5-H), 2.15(1H, br d, J=15.2 Hz, 4-H), 2.79 (1H, d, J=15.2 Hz, 4-H), 3.08 (3H, s,N--CH₃), 3.56 (3H, s, OCH₃), 3.75 (1H, dd, J=4.8, 1.4 Hz, 7-H), 5.12(1H, m, 6-H), 5.73 (1H, s, 9-H), 5.80 (1H, d, J =4.8 Hz, 8-H), 7.05-7.57(5H, m, OCONHC₆ H₅), 7.72 (1H, m, OCONHC₆ H₅); MS (FAB) m/z 409 (M+H)⁺.

Example 58

(4aR,5R,6R,7R)-6-(2-Hydroxyethylcarbamoyloxy)-7-methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (30mg=0.08 mmol) prepared in Example 47 was dissolved in toluene (0.5 ml),ethanolamine (23 μl=0.38 mmol) was added to the solution, and themixture was stirred at room temperature for 2.5 hr. Thus, the titlecompound (25 mg, 86%) was prepared.

¹ H NMR (CDCl₃) δ 0.89 (3H, s, 4a-CH₃), 1.11 (3H, d, J=7.1 Hz, 5-CH₃),1.84 (3H, br s, 3-CH₃), 2.05 (1H, m, 5-H), 2.11 (1H, br d, J=16.3 Hz,4-H), 2.76 (1H, d, J=16.3 Hz, 4-H), 3.05 (3H, s, N--CH₃), 3.41 (2H, m,OCONHCH₂ CH₂ OH), 3.52 (3H, s, OCH₃), 3.69 (1H, br d, J=4.7 Hz, 7-H),3.78 (2H, m, OCONHCH₂ CH₂ OH), 4.98 (1H, m, 6-H), 5.73 (1H, s, 9-H),5.79 (1H, d, J=4.7 Hz, 8-H), 5.92 (1H, m, OCONHCH₂ CH₂ OH); MS (FAB) m/z377 (M+H)⁺.

Example 59

(4aR,5R,6R,7R)-6-(N,N-Diethylaminocarbonyloxy)-7-methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 48 was repeated, except that the compound (50mg=0.13 mmol) prepared in Example 47 was dissolved in methylene chloride(2 ml), methyl triflate (15 μl=0.13 mmol) was added to the solution, themixture was stirred at 10° C. for 30 min, diethylamine (67 μl=0.65 mmol)was added thereto, and the mixture was stirred at room temperature for30 min. Thus, the title compound (35 mg, 70%) was prepared.

¹ H NMR (CDCl₃) δ 1.07-1.17 (6H, m, OCON(CH₂ CH₃)₂), 1.10 (3H, s,4a-CH₃), 1.16 (3H, d, J=7.2 Hz, 5-CH₃), 1.88 (3H, d, J=1.7 Hz, 3-CH₃),2.12 (1H, dq, J=7.2, 3.0 Hz, 5-H), 2.17 (1H, br d, J=15.9 Hz, 4-H), 2.82(1H, d, J=15.9 Hz, 4-H), 3.11 (3H, s, N--CH₃), 3.18-3.53 (4H, m,OCON(CH₂ CH₃)₂), 3.55 (3H, s, OCH₃), 3.70 (1H, br d, J=4.7 Hz, 7-H),5.00 (1H, m, 6-H), 5.75 (1H, s, 9-H), 5.77 (1H, d, J=4.7 Hz, 8-H); MS(FAB) m/z 387 (M+H)⁺.

Example 60

(4aR,5R,6R,7R)-7-Methoxy-6-(pyrrolidin-1-ylcarbonyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (5mg=0.01 mmol) prepared in Example 47 was dissolved in toluene (0.2 ml),pyrrolidine (10 μl=0.12 mmol) was added to the solution, and the mixturewas stirred at room temperature for 3 hr. Thus, the title compound (5mg, 100%) was prepared.

¹ H NMR (CDCl₃) δ 1.11 (3H, s, 4a-CH₃), 1.15 (3H, d, J=7.3 Hz, 5-CH₃),1.85-1.89 (4H, m, OCOC₄ H₈ N), 1.88 (3H, d, J=1.7 Hz, 3-CH₃), 2.11 (1H,dq, J=7.3, 4.5 Hz, 5-H), 2.16 (1H, br d, J=15.9 Hz, 4-H), 2.82 (1H, d,J=15.9 Hz, 4-H), 3.11 (3H, s, N--CH₃), 3.28-3.43 (4H, m, OCOC₄ H₈ N),3.56 (3H, s, OCH₃), 3.74 (1H, dd, J=4.7, 1.2 Hz, 7-H), 4.97 (1H, m,6-H), 5.74 (1H, s, 9-H), 5.77 (1H, d, J=4.7 Hz, 8-H); MS (TSP) m/z 387(M+H)⁺.

Example 61

(4aR,5R,6R,7R)-⁷-Methoxy-6-(piperidin-1-ylcarbonyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (40mg=0.10 mmol) prepared in Example 47 was dissolved in toluene (1 ml),piperidine (51 μl=0.52 mmol) was added to the solution, and the mixturewas stirred at 60° C. for 6 hr. Thus, the title compound (35 mg, 85%)was prepared.

¹ H NMR (CDCl₃) δ 1.10 (3H, s, 4a-CH₃), 1.14 (3H, d, J=7.2 Hz, 5-CH₃),1.49-1.59 (6H, m, OCOC₅ H₁₀ N), 1.88 (3H, d, J=1.9 Hz, 3-CH₃), 2.10 (1H,dq, J=7.2, 3.0 Hz, 5-H), 2.16 (1H, br d, J=16.1 Hz, 4-H), 2.82 (1H, d,J=16.1 Hz, 4-H), 3.11 (3H, s, N--CH₃), 3.32-3.47 (4H, m, OCOC₅ H₁₀ N),3.55 (3H, s, OCH₃), 3.72 (1H, dd, J=4.8, 1.2 Hz, 7-H), 5.02 (1H, m,6-H), 5.75 (1H, s, 9-H), 5.77 (1H, d, J=4.8 Hz, 8-H); MS (TSP) m/z 401(M+H)⁺.

Example 62

(4aR, 5R, 6R,7R)-7-Methoxy-6-[(2S)-2-(methoxymethyl)pyrrolidin-1-ylcarbonyloxy]-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (30mg=0.08 mmol) prepared in Example 47 was dissolved in toluene (0.8 ml),(S)-(+)-2-(methoxymethyl)pyrrolidine (72 μl=0.58 mmol) was added to thesolution, and the mixture was stirred at 60° C. for 20 hr. Thus, thetitle compound (25 mg, 75%) was prepared.

¹ H NMR (CDCl₃) δ 1.11-1.22 (6H, m, 4a-CH₃, 5-CH₃), 1.88 (3H, d, J=1.9Hz, 3-CH₃), 1.88-1.95 (4H, m, OCOC₄ H₇ N--CH₂ OCH₃), 2.12 (1H, m, 5-H),2.16 (1H, br d, J=16.3 Hz, 4-H), 2.81 (1H, d, J=16.3 Hz, 4-H), 3.11 (3H,s, N--CH₃), 3.14-3.52 (8H, m, OCOC₄ H₇ N--CH₂ OCH₃), 3.56 (3H, s, OCH₃),3.74 (1H, br d, J=4.4 Hz, 7-H), 4.97 (1H, m, 6-H), 5.74 (1H, s, 9-H),5.75 (1H, d, J=4.4 Hz, 8-H); MS (TSP) m/z 431 (M+H)⁺.

Example 63

(4aR,5R,6R,7R)-6-(4-Ethylpiperazin-1-ylcarbonyloxy)-7-methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (32mg=0.08 mmol) prepared in Example 47 was dissolved in toluene (1 ml),1-ethylpiperazine (52 μl=0.41 mmol) was added to the solution, and themixture was stirred at 60° C. for 15 hr. Thus, the title compound (41mg, quant).

¹ H NMR (CDCl₃) δ 1.09 (3H, t, J=7.2 Hz, OCOC₄ H₈ N₂ --CH₂ CH₃), 1.09(3H, s, 4a-CH₃), 1.14 (3H, d, J=7.2 Hz, 5-CH₃), 1.88 (3H, d, J=1.9 Hz,3-CH₃), 2.11 (1H, dq, J=7.2, 3.0 Hz, 5-H), 2.16 (1H, br d, J=16.2 Hz,4-H), 2.39-2.46 (4H, m, OCOC₄ H₈ N₂ --CH₂ CH₃), 2.42 (2H, q, J=7.2 Hz,OCOC₄ H₈ N₂ --CH₂ CH₃), 2.82 (1H, d, J=16.2 Hz, 4-H), 3.11 (3H, s,N--CH₃), 3.44-3.54 (4H, m, OCOC₄ H₈ N₂ --CH₂ CH₃), 3.54 (3H, s, OCH₃),3.72 (1H, dd, J=4.7, 1.2 Hz, 7-H), 5.02 (1H, m, 6-H), 5.75 (1H, s, 9-H),5.77 (1H, d, J=4.7 Hz, 8-H); MS (TSP) m/z 430 (M+H)⁺.

Example 64

(4aR,5R,6R,7R)-7-Methoxy-6-(morpholin-4-ylcarbonyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (34mg=0.09 mmol) prepared in Example 47 was dissolved in toluene (1 ml),morpholine (76 μl=0.87 mmol) was added thereto, and the mixture wasstirred at 60° C. for 2 hr. Thus, the title compound (26 mg, 74%) wasprepared.

¹ H NMR (CDCl₃) δ 1.07 (3H, s, 4a-CH₃), 1.14 (3H, d, J=7.1 Hz, 5-CH₃),1.88 (3H, d, J=1.9 Hz, 3-CH₃), 2.12 (1H, dq, J=7.1, 3.0 Hz, 5-H), 2.17(1H, br d, J=15.8 Hz, 4-H), 2.82 (1H, d, J=15.8 Hz, 4-H), 3.11 (3H, s,N--CH₃), 3.40-3.66 (8H, m, OCOC₄ H₈ NO), 3.54 (3H, s, OCH₃), 3.71 (1H,br d, J=4.8 Hz, 7-H), 5.04 (1H, m, 6-H), 5.74 (1H, s, 9-H), 5.77 (1H, d,J=4.8 Hz, 8-H); MS (TSP) m/z 403 (M+H)⁺.

Example 65

(4aR,5R,6R,7R)-6-Ethoxycarbonyloxy-7-methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (27 mg=0.09 mmol) prepared in Example 24 was dissolved inmethylene chloride (0.5 ml), ethyl chloroformate (90 μl=0.94 mmol) wasadded to the solution in the presence of pyridine (0.3 ml=3.76 mmol),and the mixture was stirred at room temperature for 27 hr. Methylenechloride was added to the reaction mixture, the mixture was washed withwater, and the organic phase was dried over sodium sulfate. The solventwas removed under reduced pressure, and the residue was purified bypreparative TLC to give the title compound (21 mg, 61%).

¹ H NMR (CDCl₃) δ 1.10 (3H, s, 4a-CH₃), 1.16 (3H, d, J=7.1 Hz, 5-CH₃),1.31 (3H, t, J=7.1 Hz, OCOOCH₂ CH₃), 1.87 (3H, d, J=1.9 Hz, 3-CH₃), 2.09(1H, dq, J=7.1, 2.8 Hz, 5-H), 2.14 (1H, br d, J=15.8 Hz, 4-H), 2.81 (1H,d, J=15.8 Hz, 4-H), 3.10 (3H, s, N--CH₃), 3.51 (3H, s, OCH₃),3.72 (1H,dd, J=4.7, 1.4 Hz, 7-H), 4.20 (2H, q, J=7.1 Hz, OCOOCH₂ CH₃), 4.89 (1H,m, 6-H), 5.73 (1H, s, 9-H), 5.76 (1H, d, J=4.7 Hz, 8-H); MS (EI) m/z 361(M)⁺.

Example 66

(4aR,5R,6R,7R)-7-Methoxy-6-phenoxycarbonyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 65 was repeated, except that the compound (27mg=0.09 mmol) prepared in Example 24 was dissolved in methylene chloride(0.5 ml), phenyl chloroformate (59 μl=0.47 mmol) was added to thesolution in the presence of pyridine (91 μl=1.13 mmol), and the mixturewas stirred at room temperature for 1.5 hr. Thus, the title compound (36mg, 94%) was prepared.

¹ H NMR (CDCl₃) δ 1.07 (3H, s, 4a-CH₃), 1.22 (3H, d, J=7.1 Hz, 5-CH₃),1.88 (3H, d, J=1.9 Hz, 3-CH₃), 2.15 (1H, dq, J=7.1, 2.8 Hz, 5-H), 2.16(1H, br d, J=15.8 Hz, 4-H), 2.83 (1H, d, J=15.8 Hz, 4-H), 3.11 (3H, s,N--CH₃), 3.52 (3H, s, OCH₃), 3.82 (1H, dd, J=4.7, 1.4 Hz, 7-H), 4.98(1H, m, 6-H), 5.75 (1H, s, 9-H), 5.79 (1H, d, J=4.7 Hz, 8-H), 7.16-7.41(5H, m, OCOOC₆ H₅); MS (EI) m/z 409 (M)⁺.

Example 67

(4aR,5R,6R,7R)-6-(Imidazol-1-ylthiocarbonyloxy)-7-methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (30 mg=0.10 mmol) prepared in Example 24 was dissolved inmethylene chloride (1 ml), 1,1'-thiocarbonyldiimidazole (27 mg=0.15mmol) was added to the solution, and the mixture was stirred at roomtemperature for 20 hr and then at 40° C. for 10 hr. Methylene chloridewas added to the reaction mixture, the mixture was washed with water,and the organic phase was dried over sodium sulfate. The solvent wasremoved under reduced pressure, and the residue was purified by columnchromatography on silica gel to give the title compound (40 mg, 97%).

¹ H NMR (CDCl₃) δ 1.19 (3H, s, 4a-CH₃), 1.20 (3H, d, J=7.0 Hz, 5-CH₃),1.90 (3H, d, J=1.9 Hz, 3-CH₃), 2.23 (1H, br d, J=16.5 Hz, 4-H), 2.35(1H, dq, J=7.0, 2.6 Hz, 5-H), 2.87 (1H, d, J=16.5 Hz, 4-H), 3.13 (3H, s,N--CH₃), 3.58 (3H, s, OCH₃), 3.85 (1H, dd, J=4.5, 1.2 Hz, 7-H), 5.77(1H, s, 9-H), 5.81 (1H, d, J=4.5 Hz, 8-H), 5.91 (1H, m, 6-H), 7.04 (1H,br s, OCSC₃ N₂), 7.59 (1H, br s, OCSC₃ N₂),8.31 (1H, br s, OCSC₃ N₂); MS(TSP) m/z 400 (M+H)⁺.

Example 68

(4aR,5R,6R,7R)-7-Methoxy-6-propylthiocarbamoyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (20 mg=0.05 mmol) prepared in Example 67 was dissolved intoluene (0.5 ml), propylamine (20 μl=0.24 mmol) was added to thesolution, and the mixture was stirred at room temperature for 30 min.Ethyl acetate was added to the reaction mixture, the mixture was washedwith water, and the organic phase was dried over sodium sulfate. Thesolvent was removed under reduced pressure, and the residue was purifiedby column chromatography on silica gel to give the title compound (16mg, 80%).

(Major)

¹ H NMR (CDCl₃) δ 0.97 (3H, t, J=7.3 Hz, OCSNHCH₂ CH₂ CH₃), 1.01 (3H, s,4a-CH₃), 1.13 (3H, d, J=7.1 Hz, 5-CH₃), 1.67 (2H, seq, J=7.3 Hz,OCSNHCH₂ CH₂ CH₃), 1.86 (3H, d, J=1.9 Hz, 3-CH₃), 2.11-2.23 (2H, m, 4-H,5-H), 2.80 (1H, d, J=15.9 Hz, 4-H), 3.08 (3H, s, N--CH₃), 3.55 (2H, brdt, J=7.3 Hz, OCSNHCH₂ CH₂ CH₃), 3.59 (3H, s, OCH₃), 3.75 (1H, dd,J=4.8, 1.8 Hz, 7-H), 5.72 (1H, s, 9-H), 5.78-5.80 (2H, m, 6-H, 8-H),6.69 (1H, m, OCSNHCH₂ CH₂ CH₃); MS (TSP) m/z 391 (M+H)⁺.

(Minor)

¹ H NMR (CDCl₃) δ 0.89 (3H, t, J=7.1 Hz, OCSNHCH₂ CH₂ CH₃), 1.12 (3H, s,4a-CH₃), 1.16 (3H, d, J=7.2 Hz, 5-CH₃), 1.52 (2H, seq, J=7.1 Hz,OCSNHCH₂ CH₂ CH₃), 1.88 (3H, d, J=1.9 Hz, 3-CH₃), 2.11-2.23 (2H, m, 4-H,5-H), 2.83 (1H, d, J=15.7 Hz, 4-H), 3.12 (3H, s, N--CH₃), 3.17 (2H, brdt, J=7.1 Hz, OCSNHCH₂ CH₂ CH₃), 3. 61 (3H, s, OCH₃), 3.79 (1H, dd,J=4.7, 1.7 Hz, 7-H), 5.76 (1H, s, 9-H), 5.78-5.80 (2H, m, 6-H, 8-H),6.69 (1H, m, OCSNHCH₂ CH₂ CH₃).

Example 69

(4aR, 5R, 6R, 7R)-7-Methoxy-6-(pyrrolidin-1-ylthiocarbonyloxy)-4a,5,6,7-tetrahydro-1,3,4a, 5-tetramethylbenz [f]indol-2(4H )-one

The procedure of Example 68 was repeated, except that the compound (20mg=0.05 mmol) prepared in Example 67 was dissolved in toluene (0.5 ml),pyrrolidine (20 μl=0.24 mmol) was added to the solution, and the mixturewas stirred at room temperature for 30 min. Thus, the title compound (16mg, 84%) was prepared.

¹ H NMR (CDCl₃) δ 1.12 (3H, s, 4a-CH₃), 1.15 (3H, d, J=7.1 Hz, 5-CH₃),1.88 (3H, d, J=1.9 Hz, 3-CH₃), 1.91-1.96 (4H, m, OCSC₄ H₈ N), 2.19 (1H,br d, J=15.9 Hz, 4-H), 2.20 (1H, dq, J=7.1, 2.8 Hz, 5-H), 2.83 (1H, d,J=15.9 Hz, 4-H), 3.11 (3H, s, N--CH₃), 3.51-3.81 (5H, m, 7-H, OCSC₄ H₈N), 3.61 (3H, s, OCH₃), 5.75 (1H, s, 9-H), 5.79 (1H, d, J=4.7 Hz, 8-H),5.82 (1H, m, 6-H); MS (TSP) m/z 403 (M+H)⁺.

Example 70

(4aR, 5R, 6R, 7R)-7-Ethoxy-6-hydroxy-4a, 5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

Ethanol (10 ml) was added to the compound (100 mg=0.32 mmol) prepared inExample 2, and the mixture was stirred at 50° C. for 3 hr. The solventwas removed under reduced pressure, and the residue was purified bypreparative TLC to give the title compound (89 mg, 92%).

¹ H NMR (CDCl₃) δ 1.09 (3H, s, 4a-CH₃), 1.18 (3H, d, J=7.1 Hz, 5-CH₃),1.19 (3H, t, J=7.0 Hz, OCH₂ CH₃ ), 1.84 (3H, d, J=1.9 Hz, 3-CH₃), 1.93(1H, dq, J=7.1, 2.8 Hz, 5-H), 2.14 (1H, br d, J=15.9 Hz, 4-H), 2.76 (1H,d, J=15.9 Hz, 4-H), 3.08 (3H, s, N--CH₃), 3.61 (1H, ap q, J=7.0 Hz, OCH₂CH₃), 3.62 (1H, ap q,J=7.0 Hz, OCH₂ CH₃), 3.79 (1H, dd, J=4.8, 1.5 Hz,7-H), 3.88 (1H, m, 6-H), 5.73 (1H, s, 9-H), 5.78 (1H, d, J=4.8 Hz, 8-H);MS (EI) m/z 303 (M)⁺ ; [α]¹⁸ _(D) -454° (c 1.0, MeOH).

Example 71

(4aR,5R,6R,7R)-6-Acetoxy-7-ethoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (32 mg=0.11 mmol) prepared in Example 70 was dissolved inpyridine (1 ml), acetyl chloride (38 μl=0.54 mmol) was added to thesolution, and the mixture was stirred at room temperature for 24 hr.Methylene chloride (20 ml) was added to the reaction mixture, themixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (20 ml×2) and saturated saline (20 ml), and the solvent wasremoved under reduced pressure. The organic phase was dried over sodiumsulfate, and the solvent was removed under reduced pressure. The residuewas purified by preparative TLC to give the title compound (18 mg, 50%).

¹ H NMR (CDCl₃) δ 1.08 (3H, s, 4a-CH₃), 1.08 (3H, d, J=7.1 Hz, 5-CH₃),1.20 (3H, t, J=7.0 Hz, OCH₂ CH₃ ), 1.86 (3H, d, J=1.9 Hz, 3-CH₃), 2.05(3H, s, OCOCH₃ ), 2.10 (1H, dq, J=7.1, 2.8 Hz, 5-H), 2.15 (1H, br d,J=15.9 Hz, 4-H), 2.78 (1H, d, J=15.9 Hz, 4-H), 3.08 (3H, s, N--CH₃),3.61 (1H, dq, J=7.0, 2.4 Hz, OCH₂ CH₃), 3.69 (1H, dd, J=4.8, 1.5 Hz,7-H), 3.81 (1H, dq, J=7.0, 2.4 Hz, OCH₂ CH₃), 5.03 (1H, m, 6-H), 5.72(1H, s, 9-H), 5.73 (1H, d, J=4.8 Hz, 8-H); MS (EI) m/z 345 (M)⁺ ; [α]¹⁸_(D) -318° (c 1.0, MeOH).

Example 72

(4aR,5R,6R,7R)-7-Ethoxy-6-propionyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (25 mg=0.08 mmol) prepared in Example 70 was dissolved inpyridine (1 ml), propionyl chloride (25 μl=0.41 mmol) was added to thesolution, and the mixture was stirred at room temperature for 18 hr.Methylene chloride (20 ml) was added to the reaction mixture, themixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (20 ml×2) and saturated saline (20 ml), and the solvent wasremoved under reduced pressure. The organic phase was dried over sodiumsulfate, and the solvent was removed under reduced pressure. The residuewas purified by preparative TLC to give the title compound (13 mg, 44%).

¹ H NMR (CDCl₃) δ 1.08 (3H, d, J=7.1 Hz, 5-CH₃), 1.09 (3H, s, 4a-CH₃),1.13 (3H, t, J=7.5 Hz, OCOCH₂ CH₃ ), 1.20 (3H, t, J=7.0 Hz, OCH₂ CH₃ ),1.86 (3H, d, J=1.9 Hz, 3-CH₃), 2.11 (1H, dq, J=7.1, 2.8 Hz, 5-H), 2.15(1H, br d, J=15.9 Hz, 4-H), 2.33 (2H, q, J=7.5 Hz, OCOCH₂ CH₃), 2.78(1H, d, J=15.9 Hz, 4-H), 3.09 (3H, s, N--CH₃), 3.62 (1H, dq, J=7.0, 2.4Hz, OCH₂ CH₃), 3.68 (1H, dd, J=4.8, 1.5 Hz, 7-H), 3.83 (1H, dq, J=7.0,2.4 Hz, OCH₂ CH₃), 5.06 (1H, m, 6-H), 5.72 (1H, s, 9-H), 5.73 (1H, d,J=4.8 Hz, 8-H); MS (EI) m/z 359 (M)⁺ ; [α]¹⁸ _(D) -267° (c 1.0, MeOH).

Example 73

(4aR,5R,6R,7R)-7-Ethoxy-6-(2-furancarbonyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (20 mg=0.07 mmol) prepared in Example 70 was dissolved inpyridine (1 ml), 2-furoyl chloride (20 μl=0.20 mmol) was added to thesolution, and the mixture was stirred at room temperature for 6 hr.Methylene chloride (20 ml) was added to the reaction mixture, themixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (20 ml×2) and saturated saline (20 ml), and the solvent wasremoved under reduced pressure. The organic phase was dried over sodiumsulfate, and the solvent was removed under reduced pressure. The residuewas purified by preparative TLC to give the title compound (25 mg, 95%).

¹ H NMR (CDCl₃) δ 1.14 (3H, d, J=7.1 Hz, 5-CH₃), 1.20 (3H, s, 4a-CH₃),1.22 (3H, t, J=7.0 Hz, OCH₂ CH₃ ), 1.87 (3H, d, J=1.9 Hz, 3-CH₃), 2.18(1H, br d, J=15.9 Hz, 4-H), 2.20 (1H, dq, J=7.1, 2.8 Hz, 5-H), 2.81 (1H,d, J=15.9 Hz, 4-H), 3.09 (3H, s, N--CH₃), 3.66 (1H, dq, J=7.0, 2.4 Hz,OCH₂ CH₃), 3.82 (1H, dd, J=4.8, 1.5 Hz, 7-H), 3.89 (1H, dq, J=7.0, 2.4Hz, OCH₂ CH₃), 5.26 (1H, m, 6-H), 5.74 (1H, s, 9-H), 5.75 (1H, d, J=4.8Hz, 8-H), 6.48 (1H, dd, J=3.5, 1.7 Hz, OCOC₄ H₃ O), 7.10 (1H, dd, J=3.5,0.8 Hz, OCOC₄ H₃ O), 7.57 (1H, dd, J=1.7, 0.8 Hz, OCOC₄ H₃ O); MS(EI)m/z 397 (M)⁺ ; [α]¹⁸ _(D) -53° (c 1.0, MeOH).

Example 74

(4aR,5R,6R,7R)-7-Ethoxy-6-(3-methylbutoxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (30 mg=0.08 mmol) prepared in Example 38 was dissolved inethanol (1 ml), methanesulfonic acid (2 μl=0.03 mmol) was added to thesolution, and the mixture was stirred at room temperature for 30 min.Methylene chloride was added to the reaction mixture, the mixture waswashed with a saturated aqueous sodium hydrogencarbonate solution, andthe organic phase was dried over sodium sulfate. The solvent was removedunder reduced pressure, and the residue was purified by preparative TLCto give the title compound (21 mg, 69%).

¹ H NMR (CDCl₃) δ 0.89 (3H, d, J=6.7 Hz, OCH₂ CH₂ CH(CH₃)₂), 0.89 (3H,d, J=6.7 Hz, OCH₂ CH₂ CH(CH₃)₂), 1.07 (3H, s, 4a-CH₃), 1.15 (3H, d,J=7.1 Hz, 5-CH₃), 1.23 (3H, t, J=7.1 Hz, OCH₂ CH₃), 1.45 (2H, m, OCH₂CH₂ CH(CH₃)₂), 1.72 (1H, seq, J=6.7 Hz, OCH₂ CH₂ CH(CH₃)₂), 1.86 (3H, d,J=1.9 Hz, 3-CH₃), 1.91 (1H, dq, J=7.1, 2.8 Hz, 5-H), 2.12 (1H, br d,J=15.9 Hz, 4-H), 2.77 (1H, d, J=15.9 Hz, 4-H), 3.09 (3H, s, N--CH₃),3.36 (1H, dt, J=9.4, 6.4 Hz, OCH₂ CH₂ CH(CH₃)₂) 3.36 (1H, m, 6-H), 3.60(1H, dq, J=9.1, 7.1 Hz, OCH₂ CH₃), 3.64 (1H, dt, J=9.4, 6.4 Hz, OCH₂ CH₂CH(CH₃)₂) 3.66 (1H, dq, J=9.1, 7.1 Hz, OCH₂ CH₃), 3.81 (1H, br d, J=4.9Hz, 7-H), 5.73 (1H, s, 9-H), 5.79 (1H, d, J=4.9 Hz, 8-H); MS (EI) m/z373 (M)⁺.

Example 75

(4aR,5R,6R,7R)-7-Ethoxy-6-(imidazol-1-ylcarbonyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 5 was repeated, except that the compound (104mg=0.34 mmol) prepared in Example 70 was dissolved in methylene chloride(3 ml), 1,1'-carbonyldiimidazole (121 mg=0.74 mmol) was added to thesolution, and the mixture was stirred at room temperature for 3 hr,followed by purification by preparative TLC to give the title compound(153 mg, quant).

¹ H NMR (CDCl₃) δ 1.18 (3H, s, 4a-CH₃), 1.21 (3H, d, J=7.2 Hz, 5-CH₃),1.26 (3H, t, J=7.0 Hz, OCH₂ CH₃), 1.90 (3H, d, J=1.9 Hz, 3-CH₃), 2.23(1H, br d, J=16.4 Hz, 4-H), 2.28 (1H, dq, J=7.2, 2.8 Hz, 5-H), 2.85 (1H,d, J=16.4 Hz, 4-H), 3.12 (3H, s, N--CH₃), 3.51 (1H, br d, J=5.4 Hz,7-H), 3.69 (1H, dq, J=9.3, 7.0 Hz, OCH₂ CH₃), 3.88 (1H, dq, J=9.3, 7.0Hz, OCH₂ CH₃), 5.25 (1H, m, 6-H), 5.76 (1H, s, 9-H), 5.77 (1H, d, J=5.4Hz, 8-H), 7.09 (1H, br s, OCOC₃ N₂), 7.38 (1H, br s, OCOC₃ N₂),8.10 (1H,br s, OCOC₃ N₂); MS (FAB) m/z 398 (M+H)⁺.

Example 76

(4aR,5R,6R,7R)-7-Ethoxy-6-propylcarbamoyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (40mg=0.10 mmol) prepared in Example 75 was prepared in toluene (1 ml),propylamine (84 μl=1.02 mmol) was added to the solution, and the mixturewas stirred at 50° C. for 2 hr, followed by purification by preparativeTLC to give the title compound (32 mg, 82%).

¹ H NMR (CDCl₃) δ 0.92 (3H, t, J=7.1 Hz, OCONHCH₂ CH₂ CH₃), 1.01 (3H, s,4a-CH₃), 1.11 (3H, d, J=7.2 Hz, 5-CH₃), 1.21 (3H, t, J=7.0 Hz, OCH₂CH₃), 1.54 (2H, seq, J=7.1 Hz, OCONHCH₂ CH₂ CH₃), 1.85 (3H, br s,3-CH₃), 2.08 (1H, dq, J=7.2, 2.6 Hz, 5-H), 2.14 (1H, br d, J=15.8 Hz,4-H), 2.77 (1H, d, J=15.8 Hz, 4-H), 3.07 (3H, s, N--CH₃), 3.16 (2H, brdt, J=7.1 Hz, OCONHCH₂ CH₂ CH₃), 3.64 (1H, dq, J=9.4, 7.0 Hz, OCH₂ CH₃),3.77 (1H, br d, J=4.9 Hz, 7-H), 3.87 (1H, dq, J=9.4, 7.0 Hz, OCH₂ CH₃),4.95 (1H, m, 6-H), 4.99 (1H, m, OCONHCH₂ CH₂ CH₃), 5.71 (1H, s, 9-H),5.74 (1H, d, J=4.9 Hz, 8-H); MS (EI) m/z 389 (M+H)⁺.

Example 77

(4aR,5R,6R,7R)-6-Hydroxy-7-(1-Methylethoxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

Isopropanol (10 ml) was added to the compound (100 mg=0.32 mmol)prepared in Example 2, and the mixture was stirred at 50° C. for 3 hr.The solvent was removed under reduced pressure, and the residue waspurified by preparative TLC to give the title compound (64 mg, 63%).

¹ H NMR (CDCl₃) δ 1.09 (3H, s, 4a-CH₃), 1.16 (6H, d, J=6.1 Hz,OCH(CH₃)₂) 1.17 (3H, d, J=7.1 Hz, 5-CH₃), 1.84 (3H, d, J=1.9 Hz, 3-CH₃),1.95 (1H, dq, J=7.1, 2.7 Hz, 5-H), 2.14 (1H, br d, J=15.9 Hz, 4-H), 2.75(1H, d, J=15.9 Hz, 4-H), 3.07 (3H, s, N--CH₃), 3.77 (1H, sep, J=6.1 Hz,OCH(CH₃)₂), 3.81 (1H, br s, 6-H), 3.85 (1H, br d, J=4.7 Hz, 7-H), 5.72(1H, d, J=4.7 Hz, 8-H), 5.73 (1H, s, 9-H); MS (EI)m/z 317 (M)⁺ ; [α]²⁸_(D) -457° (c 1.0, MeOH).

Example 78

(4aR,5R,6R,7R)-7-(1-Methylethoxy)-6-propionyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (19 mg=0.06 mmol) prepared in Example 77 was dissolved inpyridine (1 ml), propionyl chloride (18 μl=0.30 mmol) was added to thesolution, and the mixture was stirred at room temperature for 24 hr.Methylene chloride (20 ml) was added to the reaction mixture, and themixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (20 ml×2) and saturated saline (20 ml), and the solvent wasremoved under reduced pressure. The organic phase was dried over sodiumsulfate, and the solvent was removed under reduced pressure. The residuewas purified by preparative TLC to give the title compound (7 mg, 31%).

¹ H NMR (CDCl₃) δ 1.08 (3H, d, J=7.1 Hz, 5-CH₃), 1.09 (3H, s, 4a-CH₃),1.14 (3H, t, J=7.6 Hz, OCOCH₂ CH₃ ), 1.16 (3H, d, J=6.1 Hz, OCH(CH₃ )₂),1.19 (3H, d, J=6.1 Hz, OCH(CH₃ )₂), 1.86 (3H, d, J=1.9 Hz, 3-CH₃), 2.13(1H, dq, J=7.1, 2.7 Hz, 5-H), 2.16 (1H, br d, J=15.9 Hz, 4-H), 2.34 (2H,ap q,J=7.6 Hz, OCOCH₂ CH₃), 2.78 (1H, d, J=15.9 Hz, 4-H), 3.08 (3H, s,N--CH₃), 3.75 (1H, dd, J=4.8, 1.4 Hz, 7-H), 3.97 (1H, sep, J=6.1 Hz,OCH(CH₃)₂), 4.96 (1H, m, 6-H), 5.67 (1H, d, J=4.8 Hz, 8-H), 5.72 (1H, s,9-H); MS (FAB) m/z 374 (M+H)⁺ ; [α]²⁸ _(D) -304° (c 0.5, MeOH).

Example 79

(4aR,5R,6R,7R)-6-Cyclopropylcarbonyloxy-7-(1-methylethoxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 3 was repeated, except that the compound (40mg=0.13 mmol) prepared in Example 77 was dissolved in pyridine (1 ml),cyclopropanecarbonyl chloride (23 μl=0.25 mmol) was added to thesolution, and the mixture was stirred at 55° C. for 12 hr. Thus, thetitle compound (32 mg, 66%) was prepared.

¹ H NMR (CDCl₃) δ 0.80-1.04 (4H, m, OCOC₃ H₅), 1.07 (3H, d, J=7.1 Hz,5-CH₃), 1.09 (3H, s, 4a-CH₃), 1.14 (3H, d, J=6.0 Hz, OCH(CH₃)₂), 1.16(3H, d, J=6.0 Hz, OCH(CH₃)₂)1.56 (1H, m, OCOC₃ H₅), 1.85 (3H, d, J=1.9Hz, 3-CH₃), 2.11 (1H, dq, J=7.1, 2.8 Hz, 5-H), 2.14 (1H, br d, J=15.9Hz, 4-H), 2.77 (1H, d, J=15.9 Hz, 4-H), 3.07 (3H, s, N--CH₃), 3.73 (1H,dd, J=4.7, 1.4 Hz, 7-H), 3.94 (1H, sep, J=6.0 Hz, OCH(CH₃)₂), 4.93 (1H,m, 6-H), 5.6G (1H, d, J=4.7 Hz, 8-H), 5.71 (1H, s, 9-H); MS (EI) m/z 385(M)⁺ ; [α]²⁰ _(D) -231° (c 1.0, MeOH).

Example 80

(4aR,5R,6R,7R)-6-(2-Furancarbonyloxy)-7-(1-methyl)ethoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (19 mg=0.06 mmol) prepared in Example 77 was dissolved inpyridine (1 ml), 2-furoyl chloride (18 μl=0.18 mmol) was added to thesolution, and the mixture was stirred at room temperature for 20 hr.Methylene chloride (20 ml) was added to the reaction mixture, themixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (20 ml×2) and saturated saline (20 ml), and the solvent wasremoved under reduced pressure. The organic phase was dried over sodiumsulfate, and the solvent was removed under reduced pressure. The residuewas purified by preparative TLC to give the title compound (22 mg, 89%).

¹ H NMR (CDCl₃) δ 1.14 (3H, d, J=7.1 Hz, 5-CH₃), 1.17 (3H, d, J=6.1 Hz,OCH(CH₃)₂), 1.20 (3H, s, 4a-CH₃), 1.22 (3H, d, J=6.1 Hz, OCH(CH₃)₂),1.87 (3H, d, J=1.9 Hz, 3-CH₃), 2.20 (1H, br d, J=15.9 Hz, 4-H), 2.22(1H, dq, J=7.1, 2.7 Hz, 5-H), 2.82 (1H, d, J=15.9 Hz, 4-H), 3.09 (3H, s,N--CH₃), 3.89 (1H, br d, J=4.8 Hz, 7-H), 4.03 (1H, sep, J=6.1 Hz,OCH(CH₃)₂), 5.17 (1H, m, 6-H), 5.69 (1H, d, J=4.8 Hz, 8-H), 5.74 (1H, s,9-H), 6.49 (1H, dd, J=3.5, 1.8 Hz, OCOC₄ H₃ O), 7.10 (1H, d, J=3.5 Hz,OCOC₄ H₃ O), 7.56 (1H, m, OCOC₄ H₃ O); MS (EI)m/z 411 (M)⁺ ; [α]²⁸ _(D)-55° (c 1.0, MeOH).

Example 81

(4aR,5R,6R,7R)-7-(1-Methylethoxy)-6-(4-pyridinecarbonyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 3 was repeated, except that the compound (50mg=0.16 mmol) prepared in Example 77 was dissolved in pyridine (1 ml),isonicotinoyl chloride hydrochloride (56 mg=0.32 mmol) was added to thesolution, and the mixture was stirred at 55° C. for 15 hr. Thus, thetitle compound (22 mg, 33%) was prepared.

¹ H NMR (CDCl₃) δ 1.16 (3H, d, J=6.0 Hz, OCH(CH₃)₂), 1.18 (3H, d, J=7.1Hz, 5-CH₃), 1.23 (3H, s, 4a-CH₃), 1.24 (3H, d, J=6.0 Hz, OCH(CH₃)₂),1.88 (3H, d, J=1.9 Hz, 3-CH₃), 2.23 (1H, br d, J=15.9 Hz, 4-H), 2.28(1H, dq, J=7.1, 2.8 Hz, 5-H), 2.83 (1H, d, J=15.9 Hz, 4-H), 3.10 (3H, s,N--CH₃), 3.88 (1H, dd, J=4.7, 1.4 Hz, 7-H), 4.06 (1H, sep, J=6.0 Hz,OCH(CH₃)₂), 5.24 (1H, m, 6-H), 5.70 (1H, d, J=4.7 Hz, 8-H), 5.74 (1H, s,9-H), 7.70 (2H, J=6.1 Hz, OCOC₅ H₄ N), 8.77 (2H, J=6.1 Hz, OCOC₅ H₄ N);MS (EI) m/z 422 (M)⁺ ; [α]²⁰ _(D) -74° (c 1.0, MeOH).

Example 82

(4aR,5R,6R,7R)-6-Ethoxy-7-(1-methylethoxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 34 was repeated, except that the compound (52mg=0.16 mmol) prepared in Example 77 was dissolved in DMF (0.3 ml), 60%sodium hydride (42 mg=1.05 mmol) as an oil and ethyl iodide (0.16ml=1.95 mmol) were added to the solution, and the mixture was stirred at60° C. for 3.5 hr. Thus, the title compound (28 mg, 49%) was prepared.

¹ H NMR (CDCl₃) δ 1.07 (3H, s, 4a-CH₃), 1. 15 (3H, d, J=7.1 Hz, 5-CH₃),1.18 (3H, t, J=7.0 Hz, OCH₂ CH₃), 1.19 (3H, d, J=6.0 Hz, OCH(CH₃)₂),1.19 (3H, d, J=6.0 Hz, OCH(CH₃)₂), 1.86 (3H, d, J=2.0 Hz, 3-CH₃), 1.93(1H, dq, J=7.1, 2.7 Hz, 5-H), 2.12 (1H, br d, J=15.9 Hz, 4-H), 2.77 (1H,d, J=15.9 Hz, 4-H), 3.08 (3H, s, N--CH₃), 3.30 (1H, m, 6-H), 3.40 (1H,dq, J=9.2, 7.0 Hz, OCH₂ CH₃), 3.67 (1H, dq, J=9.2, 7.0 Hz, OCH₂ CH₃),3.86 (1H, br d, J=4.1 Hz, 7-H), 3.75 (1H, sep, J=6.0 Hz, OCH(CH₃)₂),5.72 (1H, s, 9-H), 5.73 (1H, d, J=4.1 Hz, 8-H); MS (EI) m/z 345 (M)⁺.

Example 83

(4aR,5R,6R,7R)-7-(1-Methylethoxy)-6-propoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 34 was repeated, except that the compound (51mg=0.16 mmol) prepared in Example 77 was dissolved in DMF (0.3 ml), 60%sodium hydride (44 mg=1.09 mmol) as an oil and propyl iodide (0.19ml=1.93 mmol) were added to the solution, and the mixture was stirred at60° C. for 4 hr. Thus, the title compound (19 mg, 34%) was prepared.

¹ H NMR (CDCl₃) δ 0.92 (3H, t, J=7.4 Hz, OCH₂ CH₂ CH₃), 1.08 (3H, s,4a-CH₃), 1.16 (3H, d, J=7.1 Hz, 5-CH₃), 1.19 (3H, d, J=6.1 Hz,OCH(CH₃)₂), 1.20 (3H, d, J=6.1 Hz, OCH(CH₃)₂), 1.57 (2H, m, OCH₂ CH₂CH₃), 1.86 (3H, d, J=1.9 Hz, 3-CH₃), 1.94 (1H, dq, J=7.1, 2.7 Hz, 5-H),2.12 (1H, br d, J=15.9 Hz, 4-H), 2.77 (1H, d, J=15.9 Hz, 4-H), 3.09 (3H,s, N--CH₃), 3.29 (1H, dt, J=8.8, 6.4 Hz, OCH₂ CH₂ CH₃), 3.29 (1H, m,6-H), 3.58 (1H, dt, J=8.8, 6.4 Hz, OCH₂ CH₂ CH₃), 3.87 (1H, dd, J=5.2,1.3 Hz, 7-H), 3.76 (1H, sep, J=6.1 Hz, OCH(CH₃)₂), 5.72 (1H, d, J=5.2Hz, 8-H), 5.73 (1H, s, 9-H); MS (EI) m/z 359 (M)⁺.

Example 84

(4aR,5R,6R,7R)-6-Butoxy-7-(1-methylethoxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 34 was repeated, except that the compound (58mg=0.18 mmol) prepared in Example 77 was dissolved in DMF (0.3 ml), 60%sodium hydride (23 mg=0.54 mmol) as an oil and butyl iodide (0.10ml=1.08 mmol) were added to the solution, and the mixture was stirred at60° C. for 3 hr. Thus, the title compound (13 mg, 19%) was prepared.

¹ H NMR (CDCl₃) δ 0.10 (3H, t, J=7.2 Hz, OCH₂ CH₂ CH₂ CH₃), 1.05 (3H, s,4a-CH₃), 1.14 (3H, d, J=7.1 Hz, 5-CH₃), 1.18 (3H, d, J=6.0 Hz,OCH(CH₃)₂), 1.19 (3H, d, J=6.0 Hz, OCH(CH₃)₂), 1.37 (2H, m, OCH₂ CH₂ CH₂CH₃), 1.52 (2H, m, OCH₂ CH₂ CH₂ CH₃), 1.85 (3H, d, J=1.9 Hz, 3-CH₃),1.92 (1H, dq, J=7.1, 2.8 Hz, 5-H), 2.11 (1H, br d, J=15.9 Hz, 4-H), 2.75(1H, d, J=15.9 Hz, 4-H), 3.07 (3H, s, N--CH₃), 3.27 (1H, m, 6-H), 3.32(1H, dt, J=8.9, 6.2 Hz, OCH₂ CH₂ CH₂ CH₃), 3.60 (1H, dt, J=8.9, 6.2 Hz,OCH₂ CH₂ CH₂ CH₃), 3.75 (1H, sep, J=6.0 Hz, OCH(CH₃)₂), 3.85 (1H, dd,J=5.2, 1.4 Hz, 7-H), 5.71 (1H, d, J=5.2 Hz, 8-H), 5.71 (1H, s, 9-H); MS(EI) m/z 373 (M)⁺ ; [α]²⁰ _(D) -308° (c 1.0, MeOH).

Example 85

(4aR,5R,6R,7R)-6-(3-Methylbutoxy)-7-(1-methylethoxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 34 was repeated, except that the compound (130mg=0.41 mmol) prepared in Example 77 was dissolved in DMF (0.7 ml), 60%sodium hydride (50 mg =1.23 mmol) as an oil and isoamyl iodide (0.32ml=2.46 mmol) were added to the solution, and the mixture was stirred at60° C. for 3 hr. Thus, the title compound (18 mg, 11%) was prepared.

¹ H NMR (CDCl₃) δ 0.87 (3H, d, J=6.6 Hz, OCH₂ CH₂ CH(CH₃)₂), 0.88 (3H,d, J=6.6 Hz, OCH₂ CH₂ CH(CH₃)₂), 1.05 (3H, s, 4a-CH₃), 1.14 (3H, d,J=7.1 Hz, 5-CH₃), 1.18 (3H, d, J=6.0 Hz, OCH(CH₃)₂), 1.19 (3H, d, J=6.0Hz, OCH(CH₃)₂), 1.43 (2H, m, OCH₂ CH₂ CH(CH₃)₂), 1.70 (1H, m, OCH₂ CH₂CH(CH₃)₂), 1.85 (3H, d, J=1.9 Hz, 3-CH₃), 1.92 (1H, dq, J=7.1, 2.8 Hz,5-H), 2.11 (1H, br d, J=15.9 Hz, 4-H), 2.75 (1H, d, J=15.9 Hz, 4-H),3.07 (3H, s, N--CH₃), 3.27 (1H, m, 6-H), 3.34 (1H, dt, J=9.1, 6.3 Hz,OCH₂ CH₂ CH(CH₃)₂), 3.62 (1H, dt, J=9.1, 6.3 Hz, OCH₂ CH₂ CH(CH₃)₂),3.75 (1H, sep, J=6.0 Hz, OCH(CH₃)₂), 3.85 (1H, dd, J=5.2, 1.4 Hz, 7-H),5.71 (1H, d, J=5.2 Hz, 8-H), 5.71 (1H, s, 9-H); MS (EI) m/z 387 (M)⁺ ;[α]²⁰ _(D) -289° (c 1.0, MeOH).

Example 86

(4aR,5R,6R,7R)-6-Cyclopropylmethoxy-7-(1-methylethoxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 34 was repeated, except that the compound (60mg=0.19 mmol) prepared in Example 77 was dissolved in DMF (0.3 ml), 60%sodium hydride (24 mg=0.57 mmol) as an oil and (bromomethyl)cyclopropane(0.11 ml=1.14 mmol) were added to the solution, and the mixture wasstirred at 60° C. for 3 hr. Thus, the title compound (15 mg, 22%) wasprepared.

¹ H NMR (CDCl₃) δ 0.10-0.54 (4H, m, OCH₂ C₃ H₅), 1.00 (1H, m, OCH₂ C₃H₅), 1.07 (3H, s, 4a-CH₃), 1.15 (3H, d, J=7.1 Hz, 5-CH₃), 1.17 (3H, d,J=6.0 Hz, OCH(CH₃)₂), 1.18 (3H, d, J=6.0 Hz, OCH(CH₃)₂), 1.85 (3H, d,J=1.9 Hz, 3-CH₃), 1.92 (1H, dq, J=7.1, 2.8 Hz, 5-H), 2.11 (1H, br d,J=15.9 Hz, 4-H), 2.76 (1H, d, J=15.9 Hz, 4-H), 3.07 (3H, s, N--CH₃),3.23 (1H, dd, J=10.2, 6.6 Hz, OCH₂ C₃ H₅), 3.33 (1H, m, 6-H), 3.47 (1H,dd, J=10.2, 6.6 Hz, OCH₂ C₃ H₅), 3.73 (1H, sep, J=6.0 Hz, OCH(CH₃)₂),3.84 (1H, dd, J=5.2, 1.4 Hz, 7-H), 5.71 (1H, s, 9-H), 5.72 (1H, d, J=5.2Hz, 8-H); MS (EI) m/z 371 (M)⁺ ; [α]²⁰ _(D) -515° (c 1.0, MeOH).

Example 87

(4aR,5R,6R,7R)-6-(Imidazol-1-ylcarbonyloxy)-7-(1-methylethoxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 5 was repeated, except that the compound (100mg=0.32 mmol) prepared in Example 77 was dissolved in methylene chloride(2 ml), 1,1'-carbonyldiimidazole (204 mg=1.26 mmol) was added to thesolution, and the mixture was stirred at room temperature for 3 hr.Thus, the title compound (120 mg, 93%) was prepared.

¹ H NMR (CDCl₃) δ 1.18 (3H, s, 4a-CH₃), 1.21 (3H, d, J=6.1 Hz,OCH(CH₃)₂), 1.22 (3H, d, J=7.3 Hz, 5-CH₃), 1.25 (3H, d, J=6.1 Hz,OCH(CH₃)₂), 1.90 (3H, d, J=1.9 Hz, 3-CH₃), 2.23 (1H, br d, J=15.7 Hz,4-H), 2.30 (1H, dq, J=7.3, 2.6 Hz, 5-H), 2.85 (1H, d, J=15.7 Hz, 4-H),3.12 (3H, s, N--CH₃), 3.98 (1H, dd, J=4.8, 1.1 Hz, 7-H), 4.01 (1H, sep,J=6.1 Hz, OCH(CH₃)₂), 5.16 (1H, m, 6-H), 5.71 (1H, d, J=4.8 Hz, 8-H),5.75 (1H, s, 9-H), 7.09 (1H, br s, OCOC₃ N₂), 7.39 (1H, br s,OCOC₃N₂),8.10 (1H, br s, OCOC₃ N₂); MS (TSP) m/z 412 (M+H)⁺.

Example 88

(4aR,5R,6R,7R)-6-Methylcarbamoyloxy-7-(1-methylethoxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (50mg=0.12 mmol) prepared in Example 87 was dissolved in THF (0.4 ml), a 2M methylamine/THF solution (0.61 ml=1.22 mmol) was added to thesolution, and the mixture was stirred at room temperature for 2 hr,followed by purification by preparative TLC. Thus, the title compound(41 mg, 89%) was prepared.

¹ H NMR (CDCl₃) δ 0.98 (3H, s, 4a-CH₃), 1.11 (3H, d, J=7.1 Hz, 5-CH₃),1.17 (3H, d, J=6.3 Hz, OCH(CH₃)₂), 1.20 (3H, d, J=6.3 Hz, OCH(CH₃)₂),1.85 (3H, br s, 3-CH₃), 2.14 (1H, br d, J=16.2 Hz, 4-H), 2.15 (1H, dq,J=7.1, 2.4 Hz, 5-H), 2.76 (1H, d, J=16.2 Hz, 4-H), 2.82 (3H, d, J=4.7Hz, OCONHCH₃), 3.06 (3H, s, N--CH₃), 3.83 (1H, br d, J=5.0 Hz, 7-H),4.02 (1H, sep, J=6.3 Hz, OCH(CH₃)₂), 4.85 (1H, m, 6-H), 5.04 (1H, m,OCONHCH₃), 5.68 (1H, d, J=5.0 Hz, 8-H), 5.70 (1H, s, 9-H); MS (FAB) m/z375 (M+H)⁺.

Example 89

(4aR,5R,6R,7R)-7-(1-Methylethoxy)-6-propylcarbamoyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (44mg=0.11 mmol) prepared in Example 87 was dissolved in toluene (1 ml),propylamine (43 μl=0.52 mmol) was added to the solution, and the mixturewas stirred at 60° C. for 3 hr. Thus, the title compound (30 mg, 70%)was prepared.

¹ H NMR (CDCl₃) 0.93 (3H, t, J=7.3 Hz, OCONHCH₂ CH₂ CH₃), 1.03 (3H, s,4a-CH₃), 1.12 (3H, d, J=7.1 Hz, 5-CH₃), 1.18 (3H, d, J=6.5 Hz,OCH(CH₃)₂), 1.21 (3H, d, J=6.5 Hz, OCH(CH₃)₂), 1.55 (2H, seq, J=7.3 Hz,OCONHCH₂ CH₂ CH₃), 1.86 (3H, br s, 3-CH₃), 2.12 (1H, br q, J=7.1 Hz,5-H), 2.16 (1H, br d, J=16.6 Hz, 4-H), 2.78 (1H, d, J=16.6 Hz, 4-H),3.08 (3H, s, N--CH₃), 3.16 (2H, br dt, J=7.3 Hz, OCONHCH₂ CH₂ CH₃), 3.84(1H, br d, J=4.7 Hz, 7-H), 4.03 (1H, sep, J=6.5 Hz, OCH(CH₃)₂), 4.09(1H, m, OCONHCH₂ CH₂ CH₃), 4.86 (1H, m, 6-H), 5.69 (1H, d, J=4.7 Hz,8-H), 5.72 (1H, s, 9-H); MS (TSP) m/z 403 (M+H)⁺.

Example 90

(4aR,5R,6R,7R)-6-Hydroxy-7-(2-methylpropoxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 24 was repeated, except that the compound (100mg=0.32 mmol) prepared in Example 2 was dissolved in isopropanol (3 ml)and the mixture was stirred at 50° C. for 3 hr, followed by columnchromatography on silica gel. Thus, the title compound (85 mg, 82%) wasprepared.

¹ H NMR (CDCl₃) δ 0.90 (3H, d, J=6.7 Hz, OCH₂ CH(CH₃)₂), 0.91 (3H, d,J=6.7 Hz, OCH₂ CH(CH₃)₂), 1.12 (3H, s, 4a-CH₃), 1.19 (1H, m, OCH₂CH(CH₃)₂), 1.21 (3H, d, J=7.3 Hz, 5-CH₃), 1.87 (3H, d, J=2.1 Hz, 3-CH₃),1.96 (1H, dq, J=7.3, 2.5 Hz, 5-H), 2.17 (1H, br d, J=15.8 Hz, 4-H), 2.79(1H, d, J=15.8 Hz, 4-H), 3.11 (3H, s, N--CH₃), 3.12-3.36 (2H, m, OCH₂CH(CH₃)₂), 3.79 (1H, dd, J=4.7, 1.7 Hz, 7-H), 3.90 (1H, m, 6-H), 5.79(1H, s, 9-H), 5.81 (1H, d, J=4.7 Hz, 8-H); MS (FAB) m/z 331 (M)⁺.

Example 91

(4aR,5R,6R,7R)-6-(Imidazol-1-ylcarbonyloxy)-7-(2-methylpropoxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 5 was repeated, except that the compound (180mg=0.54 mmol) prepared in Example 90 was dissolved in methylene chloride(4 ml), 1,1'-carbonyldiimidazole (175 mg=1.08 mmol) was added to thesolution, and the mixture was stirred at room temperature for 3 hr.Thus, the title compound (190 mg, 82%) was prepared.

¹ H NMR (CDCl₃) δ 0.91-0.96 (6H, m, OCH₂ CH(CH₃)₂), 1.18 (3H, s,4a-CH₃), 1.19 (1H, m, OCH₂ CH(CH₃)₂), 1.21 (3H, d, J=7.0 Hz, 5-CH₃),1.90(3H, br s, 3-CH₃), 2.23 (1H, br d, J=15.9 Hz, 4-H), 2.26 (1H, m, 5-H),2.85 (1H, d, J=15.9 Hz, 4-H), 3.12 (3H, s, N--CH₃), 3.42-3.53 (2H, m,OCH₂ CH(CH₃)₂), 3.88 (1H, m, 7-H), 5.24 (1H, m, 6-H), 5.77 (2H, m, 8-H,9-H), 7.08 (1H, br s, OCOC₃ N₂), 7.38 (1H, br s, OCOC₃ N₂), 8.10 (1H, brs, OCOC₃ N₂); MS (TSP) m/z 426 (M+H)⁺.

Example 92

(4aR,5R,6R,7R)-7-(2-Methylpropoxy)-6-propylcarbamoyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (36mg=0.08 mmol) prepared in Example 91 was dissolved in toluene (1 ml),propylamine (69 μl=0.84 mmol) was added to the solution, and the mixturewas stirred at room temperature for 15 hr. Thus, the title compound (27mg, 77%) was prepared.

¹ H NMR (CDCl₃) δ 0.91 (3H, d, J=6.6 Hz, OCH₂ CH(CH₃)₂), 0.92 (3H, d,J=6.6 Hz, OCH₂ CH(CH₃)₂), 0.95 (3H, t, J=7.0 Hz, OCONHCH₂ CH₂ CH₃), 1.04(3H, s, 4a-CH₃), 1.12 (1H, m, OCH₂ CH(CH₃)₂), 1.12 (3H, d, J=7.0 Hz,5-CH₃), 1.55 (2H, seq, J=7.0 Hz, OCONHCH₂ CH₂ CH₃), 1.87 (3H, br s,3-CH₃), 2.09 (1H, dq, J=7.0, 2.3 Hz, 5-H), 2.16 (1H, br d, J=16.2 Hz,4-H), 2.79 (1H, d, J=16.2 Hz, 4-H), 3.09 (3H, s, N--CH₃), 3.17 (2H, brdt, J=7.0 Hz, OCONHCH₂ CH₂ CH₃), 3.40 (1H, dd, J=9.2, 6.8 Hz, OCH₂CH(CH₃)₂), 3.53 (1H, dd, J=9.2, 6.8 Hz, OCH₂ CH(CH₃)₂), 3.76 (1H, br d,J=4.7 Hz, 7-H), 4.89 (1H, m, OCONHCH₂ CH₂ CH₃), 4.95 (1H, m, 6-H), 5.74(1H, s, 9-H), 5.77 (1H, d, J=4.7 Hz, 8-H); MS (TSP) m/z 417 (M+H)⁺.

Example 93

(4aR,5R,6R,7R)-7-Cyclopropylmethoxy-6-hydroxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 24 was repeated, except that the compound (200mg=0.63 mmol) prepared in Example 2 was dissolved in cyclopropanemethanol (4 ml) and the solution was stirred at 50 for 8 hr, followed bychromatography on silica gel. Thus, the title compound (190 mg, 92%) wasprepared.

¹ H NMR (CDCl₃) δ 0.20-0.57 (4H, m, OCH₂ C₃ H₅), 1.07 (1H, m, OCH₂ C₃H₅), 1.12 (3H, s, 4a-CH₃), 1.20 (3H, d, J=7.3 Hz, 5-CH₃), 1.87 (3H, d,J=1.9 Hz, 3-CH₃), 1.97 (1H, dq, J=7.3, 2.5 Hz, 5-H), 2.17 (1H, br d,J=15.9 Hz, 4-H), 2.78 (1H, d, J=15.9 Hz, 4-H), 3.11 (3H, s, N--CH₃),3.41 (1H, d, J=6.9 Hz, OCH₂ C₃ H₅), 3.42 (1H, d, J=6.9 Hz, OCH₂ C₃ H₅),3.86 (1H, dd, J=4.7, 1.6 Hz, 7-H), 3.92 (1H, m, 6-H), 5.76 (1H, s, 9-H),5.82 (1H, d, J=4.7 Hz, 8-H); MS (TSP) m/z 330 (M+H)⁺.

Example 94

(4aR,5R,6R,7R)-7-Cyclopropylmethoxy-6-(imidazol-1-ylcarbonyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]lindol-2(4H)-one

The procedure of Example 5 was repeated, except that the compound (100mg=0.30 mmol) prepared in Example 93 was dissolved in methylene chloride(2 ml), 1,1'-carbonyldiimidazole (97 mg=0.60 mmol) was added to thesolution, and the mixture was stirred at room temperature for 3 hr.Thus, the title compound (120 mg, 93%).

¹ H NMR (CDCl₃) δ 0.25-0.59 (4H, m, OCH₂ C₃ H₅), 1.11 (1H, m, OCH₂ C₃H₅), 1.18 (3H, s, 4a-CH₃), 1.22 (3H, d, J=7.2 Hz, 5-CH₃), 1.90 (3H, d,J=1.9 Hz, 3-CH₃), 2.23 (1H, br d, J=16.2 Hz, 4-H), 2.31 (1H, dq, J=7.2,2.8 Hz, 5-H), 2.85 (1H, d, J=16.2 Hz, 4-H), 3.12 (3H, s, N--CH₃), 3.50(1H, dd, J=10.2, 6.9 Hz, OCH₂ C₃ H₅), 3.63 (1H, dd, J=10.2, 6.9 Hz, OCH₂C₃ H₅), 3.96 (1H, br d, J=4.6 Hz, 7-H), 5.24 (1H, m, 6-H), 5.76 (1H, s,9-H), 5.79 (1H, d, J=4.6 Hz, 8-H), 7.08 (1H, br s, OCOC₃ N₂), 7.38 (1H,br s, OCOC₃ N₂),8.10 (1H, br s, OCOC₃ N₂); MS (TSP) m/z 424 (M+H)⁺.

Example 95

(4aR,5R,6R,7R)-7-Cyclopropylmethoxy-6-propylcarbamoyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (40mg=0.09 mmol) prepared in Example 94 was dissolved in toluene (1 ml),propylamine (76 μl=0.92 mmol) was added to the solution, and the mixturewas stirred at 60° C. for 15 hr. Thus, the title compound (15 mg, 38%)was prepared.

¹ H NMR (CDCl₃) δ 0.22-0.55 (4H, m, OCH₂ C₃ H₅), 0.93 (3H, t, J=7.3 Hz,OCONHCH₂ CH₂ CH₃), 1.04 (3H, s, 4a-CH₃), 1.08 (1H, m, OCH₂ C₃ H₅), 1.12(3H, d, J=7.1 Hz, 5-CH₃), 1.54 (2H, seq, J=7.3 Hz, OCONHCH₂ CH₂ CH₃),1.89 (3H, br s, 3-CH₃), 2.12 (1H, br q, J=7.1 Hz, 5-H), 2.16 (1H, br d,J=15.9 Hz, 4-H), 2.78 (1H, d, J=15.9 Hz, 4-H), 3.09 (3H, s,N--CH₃), 3.13(2H, br dt, J=7.3 Hz, OCONHCH₂ CH₂ CH₃), 3.47 (1H, dd, J=10.2, 6.9 Hz,OCH₂ C₃ H₅), 3.61 (1H, dd, J=10.2, 6.9 Hz, OCH₂ C₃ H₅), 3.81 (1H, br d,J=6.1 Hz, 7-H), 4.84 (1H, m, 6-H), 4.87 (1H, m, OCONHCH₂ CH₂ CH₃) 5.73(1H, s, 9-H), 5.78 (1H, d, J=6.1 Hz, 8-H); MS (TSP) m/z 415 (M+H)⁺.

Example 96

(4aR, 5R, 6R, 7R)-6-Hydroxy-7-methylthio-4a, 5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (152 mg=0.48 mmol) prepared in Example 2 was dissolved inmethylene chloride (3 ml), methanesulfonic acid (6 μl=0.10 mmol) wasadded to the solution in the presence of methylmercaptan (250 mg=5.20mmol), and the mixture was stirred at 0 for 30 min. Methylene chloridewas added to the reaction mixture, the mixture was washed with saturatedsaline, and the organic phase was dried over sodium sulfate. The solventwas removed under reduced pressure, and the residue was purified bychromatography on silica gel to give the title compound (83 mg, 57%).

¹ H NMR (CDCl₃) δ 1.15 (3H, s, 4a-CH₃), 1.22 (3H, d, J=7.3 Hz, 5-CH₃),1.88 (3H, d, J=2.0 Hz, 3-CH₃), 2.12 (1H, br d, J=15.2 Hz, 4-H), 2.13(1H, dq, J=7.3, 2.3 Hz, 5-H), 2.19 (3H, s, S--CH₃), 2.81 (1H, d, J=15.2Hz, 4-H), 3.11 (3H, s, N--CH₃), 3.45 (1H, br d, J=5.5 Hz, 7-H), 4.00(1H, m, 6-H), 5.74 (1H, d, J=5.5 Hz, 8-H), 5.75 (1H, s, 9-H); MS (EI)m/z 305 (M)⁺.

Example 97

(4aR,5R,6R,7R)-7-Methylthio-6-propionyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 3 was repeated, except that the compound (21mg=0.07 mmol) prepared in Example 96 was dissolved in methylene chloride(0.4 ml), propionyl chloride (26 μl=0.30 mmol) was added to the solutionin the presence of pyridine (54 μl=0.67 mmol), and the mixture wasstirred at room temperature for 3 hr. Thus, the title compound (17 mg,71%) was prepared.

¹ H NMR (CDCl₃) δ 1.12 (3H, d, J=7.0 Hz, 5-CH₃), 1.14 (3H, s, 4a-CH₃)1.15 (3H, t, J=7.6 Hz, OCOCH₂ CH₃), 1.88 (3H, d, J=1.9 Hz, 3-CH₃), 2.15(1H, br d, J=15.8 Hz, 4-H), 2.31 (3H, s, S--CH₃), 2.35 (1H, dq, J=7.0,2.0 Hz, 5-H), 2.35 (2H, q, J=7.6 Hz, OCOCH₂ CH₃), 2.83 (1H, d, J=15.8Hz, 4-H), 3.11 (3H, s, N--CH₃), 3.41 (1H, br d, J=4.9 Hz, 7-H), 5.11(1H, m, 6-H), 5.69 (1H, d, J=4.9 Hz, 8-H), 5.73 (1H, s, 9-H); MS (EI)m/z 361 (M)⁺.

Example 98

(4aR,5R,6R,7R)-6-Benzoyloxy-7-methylthio-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 3 was repeated, except that the compound (20mg=0.07 mmol) prepared in Example 96 was dissolved in methylene chloride(0.5 ml), benzoyl chloride (34 μl=0.29 mmol) was added to the solutionin the presence of 4-dimethylaminopyridine (46 mg=0.37 mmol), and themixture was stirred at room temperature for 2 hr. Thus, the titlecompound (26 mg, 96%) was prepared.

¹ H NMR (CDCl₃) δ 1.21 (3H, d, J=7.1 Hz, 5-CH₃), 1.30 (3H, s, 4a-CH₃),1.91 (3H, d, J=1.9 Hz, 3-CH₃), 2.21 (1H, br d, J=15.9 Hz, 4-H), 2.39(3H, s, S--CH₃), 2.49 (1H, dq, J=7.1, 2.5 Hz, 5-H), 2.89 (1H, d, J=15.9Hz, 4-H), 3.13 (3H, s, N--CH₃), 3.57 (1H, br d, J=4.9 Hz, 7-H), 5.38(1H, m, 6-H), 5.74 (1H, d, J=4.9 Hz, 8-H), 5.76 (1H, s, 9-H), 7.42-7.49(2H, m, OCOC₆ H₅), 7.58 (1H, m, OCOC₆ H₅), 7.98-8.01 (2H, m, OCOC₆ H₅);MS (EI) m/z 409 (M)⁺.

Example 99

(4aR,5R,6R,7R)-6-(Imidazol-1-ylcarbonyloxy)-7-methylthio-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 5 was repeated, except that the compound (18mg=0.06 mmol) prepared in Example 96 was dissolved in methylene chloride(0.6 ml), 1,1'-carbonyldiimidazole (21 mg=0.13 mmol) was added to thesolution, and the mixture was stirred at room temperature for 3 hr,followed by purification by preparative TLC to give the title compound(25 mg, 100%).

¹ H NMR (CDCl₃) δ 1.21 (3H, s, 4a-CH₃), 1.24 (3H, d, J=7.1 Hz, 5-CH₃),1.90 (3H, d, J=1.9 Hz, 3-CH₃), 2.21 (1H, br d, J=15.3 Hz, 4-H), 2.35(3H, s, S--CH₃), 2.51 (1H, dq, J=7.1, :2.4 Hz, 5-H), 2.88 (1H, d, J=15.3Hz, 4-H), 3.12 (3H, s, N--CH₃), 3.61 (1H, br d, J=5.1 Hz, 7-H), 5.31(1H, m, 6-H), 5.71 (1H, d, J=5.1 Hz, 8-H), 5.75 (1H, s, 9-H), 7.08 (1H,br s, OCOC₃ H₃ N₂), 7.38 (1H, br s, OCOC₃ H₃ N₂), 8.10 (1H, br s, OCOC₃H₃ N₂); MS (FAB) m/z 400 (M+H)⁺.

Example 100

(4aR,5R,6R,7R)-7-Ethylthio-6-hydroxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethrlbenz[f]indol-2(4H)-one

The procedure of Example 96 was repeated, except that the compound (488mg=1.54 mmol) prepared in Example 2 was dissolved in methylene chloride(10 ml), methanesulfonic acid (40 μl=0.62 mmol) was added to thesolution in the presence of ethyl mercaptan (1.10 ml=14.9 mmol), and themixture was stirred at room temperature for 20 min. Thus, the titlecompound (477 mg, 97%) was prepared.

¹ H NMR (CDCl₃) δ 1.14 (3H, s, 4a-CH₃), 1.21 (3H, d, J=7.2 Hz, 5-CH₃),1.29 (3H, t, J=7.4 Hz, S--CH₂ CH₃), 1.87 (3H, d, J=1.9 Hz, 3-CH₃), 2.13(1H, br d, J=15.7 Hz, 4-H), 2.14 (1H, dq, J=7.2, 2.1 Hz, 5-H), 2.62 (1H,dq, J=12.5, 7.4 Hz, S--CH₂ CH₃), 2.68 (1H, dq, J=12.5, 7.4 Hz, S--CH₂CH₃), 2.80 (1H, d, J=15.7 Hz, 4-H), 3.10 (3H, s, N--CH₃), 3.52 (1H, dd,J=4.9, 1.5 Hz, 7-H), 3.98 (1H, m, 6-H), 5.74 (1H, d, J=4.9 Hz, 8-H),5.75 (1H, s, 9-H); MS (EI) m/z 319 (M)⁺.

Example 101

(4aR,5R,6R,7R)-7-Ethylthio-6-propionyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 3 was repeated, except that the compound (31mg=0.10 mmol) prepared in Example 100 was dissolved in methylenechloride (0.6 ml), propionyl chloride (38 μl=0.44 mmol) was added to thesolution in the presence of pyridine (94 μl=1.16 mmol), and the mixturewas stirred at room temperature for 3 hr. Thus, the title compound (30mg, 82%) was prepared.

¹ H NMR (CDCl₃) δ 1.11 (3H, d, J=7.0 Hz, 5-CH₃), 1.13 (3H, s, 4a-CH₃),1.15 (3H, t, J=7.5 Hz, OCOCH₂ CH₃), 1.31 (3H, t, J=7.4 Hz, S--CH₂ CH₃),1.88 (3H, d, J=1.9 Hz, 3-CH₃), 2.14 (1H, br d, J=16.4 Hz, 4-H), 2.35(2H, ap q, J=7.5 Hz, OCOCH₂ CH₃), 2.36 (1H, br q, J=7.0 Hz, 5-H), 2.75(1H, dq, J=12.7, 7.4 Hz, S--CH₂ CH₃), 2.82 (1H, d, J=16.4 Hz, 4-H), 2.86(1H, dq, J=12.7, 7.4 Hz, S--CH₂ CH₃), 3.11 (3H, s, N--CH₃), 3.49 (1H, brd, J=5.0 Hz, 7-H), 5.08 (1H, m, 6-H), 5.68 (1H, d, J=5.0 Hz, 8-H), 5.72(1H, s, 9-H); MS (EI) m/z 375 (M)⁺.

Example 102

(4aR,5R,6R,7R)-6-Benzoyloxy-7-ethylthio-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 3 was repeated, except that the compound (30mg=0.10 mmol) prepared in Example 100 was dissolved in methylenechloride (0.6 ml), benzoyl chloride (50 μl=0.43 mmol) was added to thesolution in the presence of 4-dimethylaminopyridine (64 mg=0.53 mmol),and the mixture was stirred at room temperature for 3 hr. Thus, thetitle compound (45 mg, 100%) was prepared.

¹ H NMR (CDCl₃) δ 1.20 (3H, d, J=7.2 Hz, 5-CH,), 1.30 (3H, s, 4a-CH₃),1.35 (3H, t, J=7.4 Hz, S--CH₂ CH₃), 1.90 (3H, d, J=1.9 Hz, 3-CH₃), 2.21(1H, br d, J=15.9 Hz, 4-H), 2.50 (1H, dq, J=7.2, 2.4 Hz, 5-H), 2.83 (1H,dq, J=12.6, 7.4 Hz, S--CH₂ CH₃), 2.88 (1H, d, J=15.9 Hz, 4-H), 2.95 (1H,dq, J=12.6, 7.4 Hz, S--CH₂ CH₃), 3.12 (3H, s, N--CH₃), 3.65 (1H, br d,J=5.0 Hz, 7-H), 5.36 (1H, m, 6-H), 5.73 (1H, d, J=5.0 Hz, 8-H), 5.76(1H, s, 9-H), 7.42-7.47 (2H, m, OCOC₆ H₅), 7.58 (1H, m, OCOC₆ H₅),7.98-8.02 (2H, m, OCOC₆ H₅); MS (EI) m/z 422 (M-H)⁺.

Example 103

(4aR,5R,6R,7R)-6-Butoxy-7-ethylthio-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 96 was repeated, except that the compound (37mg=0.11 mmol) prepared in Example 37 was dissolved in methylene chloride(0.8 ml), methanesulfonic acid (3 μl=0.04 mmol) was added to thesolution in the presence of ethylmercaptan (80 μl=1.08 mmol), and themixture was stirred at room temperature for 30 min, followed bypurification by preparative TLC. Thus, the title compound (37 mg, 62%)was prepared.

¹ H NMR (CDCl₃) δ 0.90 (3H, t, J=7.3 Hz, OCH₂ CH₂ CH₂ CH₃), 1.09 (3H, s,4a-CH₃), 1.16 (3H, d, J=7.1 Hz, 5-CH₃), 1.30 (3H, t, J=7.4 Hz, S--CH₂CH₃), 1.37 (2H, m, OCH₂ CH₂ CH₂ CH₃) 1.53 (2H, m, OCH₂ CH₂ CH₂ CH₃) 1.86(3H, d J=1.9 Hz, 3-CH₃), 2.08 (1H, br d, J=15.1 Hz, 4-H), 2.09 (1H, dq,J=7.1, 2.6 Hz, 5-H), 2.61 (1H, dq, J=11.4, 7.4 Hz, S--CH₂ CH₃), 2.66(1H, dq, J=11.4, 7.4 Hz, S--CH₂ CH₃), 2.78 (1H, d, J=15.1 Hz, 4-H), 3.09(3H, s, N--CH₃), 3.28 (1H, dt, J=8.9, 6.2 Hz, OCH₂ CH₂ CH₂ CH₃)3.44 (1H,m, 6-H), 3.55 (1H, br d, J=4.8 Hz, 7-H), 3.58 (1H, dt, J=8.9, 6.2 Hz,OCH₂ CH₂ CH₂ CH₃),5.71 (1H, d, J=4.8 Hz, 8-H), 5.72 (1H, s, 9-H); MS(EI) m/z 375 (M)⁺.

Example 104

(4aR,5R,6R,7R)-7-Ethylthio-6-(3-methylbutoxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 96 was repeated, except that the compound (20mg=0.06 mmol) prepared in Example 38 was dissolved in methylene chloride(0.5 ml), methanesulfonic acid (1 μl=0.02 mmol) was added to thesolution in the presence of ethylmercaptan (45 μl=0.61 mmol), and themixture was stirred at room temperature for 20 min, followed bypurification by preparative TLC to give the title compound (19 mg, 89%).

¹ H NMR (CDCl₃) δ 0.89 (3H, d, J=6.7 Hz, OCH₂ CH₂ CH(CH₃)₂), 0.90 (3H,d, J=6.7 Hz, OCH₂ CH₂ CH(CH₃)₂), 1.09 (3H, s, 4a-CH₃), 1.16 (3H, d,J=7.1 Hz, 5-CH₃), 1.31 (3H, t, J=7.4 Hz, S--CH₂ CH₃), 1.44 (2H, m, OCH₂CH₂ CH(CH₃)₂) 1.70 (1H, seq, J=6.7 Hz, OCH₂ CH₂ CH(CH₃)₂) 1.87 (3H, d,J=1.9 Hz, 3-CH₃) 2.09 (1H, br d, J=15.1 Hz, 4-H), 2.09 (1H, dq, J=7.1,2.5 Hz, 5-H), 2.66 (1H, dq, J=12.7, 7.4 Hz, S--CH₂ CH₃), 2.67 (1H, dq,J=12.7, 7.4 Hz, S--CH₂ CH₃), 2.79 (1H, d, J=15.1 Hz, 4-H), 3.09 (3H, s,N--CH₃), 3.30 (1H, dt, J=9.1, 6.5 Hz, OCH₂ CH₂ CH(CH₃)₂), 3.44 (1H, m,6-H), 3.56 (1H, br d, J=4.7 Hz, 7-H), 3.60 (1H, dt, J=9.1, 6.5 Hz, OCH₂CH₂ CH(CH₃)₂), 5.71 (1H, d, J=4.7 Hz, 8-H), 5.72 (1H, s, 9-H); MS (EI)m/z 389 (M)⁺.

Example 105

(4aR,5R,6R,7R)-6-Cyclopropylmethoxy-7-ethylthio-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 96 was repeated, except that the compound (37mg=0.11 mmol) prepared in Example 40 was dissolved in methylene chloride(0.8 ml), methanesulfonic acid (3 μl=0.04 mmol) was added to thesolution in the presence of ethylmercaptan (79 μl=1.07 mmol), and themixture was stirred at room temperature for 20 min, followed bypurification by preparative TLC. Thus, the title compound (19 mg, 47%)was prepared.

¹ H NMR (CDCl₃) δ 0.18-0.24 (2H, m, OCH₂ C₃ H₅), 0.45-0.53 (2H, m, OCH₂C₃ H₅), 1.03 (1H, m, OCH₂ C₃ H₅), 1.11 (3H, s, 4a-CH₃), 1.17 (3H, d,J=7.1 Hz, 5-CH₃), 1.30 (3H, t, J=7.4 Hz, S--CH₂ CH₃), 1.87 (3H, d, J=1.9Hz, 3-CH₃), 2.09 (1H, br d, J=15.1 Hz, 4-H), 2.10 (1H, dq, J=7.1, 2.5Hz, 5-H), 2.62 (1H, dq, J=12.5, 7.4 Hz, S--CH₂ CH₃), 2.63 (1H, dq,J=12.5, 7.4 Hz, S--CH₂ CH₃), 2.79 (1H, d, J=15.1 Hz, 4-H), 3.09 (3H, s,N--CH₃), 3.21 (1H, dd, J=10.0, 6.4 Hz, OCH₂ C₃ H₅), 3.45 (1H, dd,J=10.0, 6.4 Hz, OCH₂ C₃ H₅), 3.50 (1H, m, 6-H), 3.54 (1H, br d, J=4.4Hz, 7-H), 5.72 (1H, d, J=4.4 Hz, 8-H), 5.72 (1H, s, 9-H); MS (EI) m/z373 (M)⁺.

Example 106

(4aR,5R,6R,7R)-7-Ethylthio-6-(imidazol-1-ylcarbonyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 5 was repeated, except that the compound (152mg=0.48 mmol) prepared in Example 100 was dissolved in methylenechloride (3 ml), 1,1'-carbonyldiimidazole (156 mg=0.96 mmol) was addedto the solution, and the mixture was stirred at room temperature for 2hr. Thus, the title compound (213 mg, 100%) was prepared.

¹ H NMR (CDCl₃) δ 1.21 (3H, s, 4a-CH₃), 1.23 (3H, d, J=7.1 Hz, 5-CH₃),1.35 (3H, t, J=7.4 Hz, S--CH₂ CH₃), 1.95 (3H, d, J=1,9 Hz, 3-CH₃), 2.21(1H, br d, J=16.0 Hz, 4-H), 2.53 (1H, dq, J=7.1, 2.3 Hz, 5-H), 2.78 (1H,dq, J=12.6, 7.4 Hz, S--CH₂ CH₃), 2.88 (1H, d, J=16.0 Hz, 4-H), 2.89 (1H,dq, J=12.6, 7.4 Hz, S--CH₂ CH₃), 3.13 (3H, s, N--CH₃), 3.70 (1H, br d,J=4.9 Hz, 7-H), 5.29 (1H, m, 6-H), 5.70 (1H, d, J=4.9 Hz, 8-H), 5.74(1H, s, 9-H), 7.09 (1H, br s, OCOC₃ H₃ N₂), 7.39 (1H, br s,OCOC₃ H₃ N₂),8.11 (1H, br s, OCOC₃ H₃ N₂); MS (FAB) m/z 414 (M+H)⁺.

Example 107

(4aR,5R,6R,7R)-7-Ethylthio-6-propylcarbamoyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (46mg=0.11 mmol) prepared in Example 106 was dissolved in toluene (1 ml),propylamine (90 μl=1.10 mmol) was added to the solution, and the mixturewas stirred at room temperature for 2 hr and at 50° C. for 4 hr,followed by purification by preparative TLC to give the title compound(33 mg, 75%).

¹ H NMR (CDCl₃) δ 0.93 (3H, t, J=7.1 Hz, OCONHCH₂ CH₂ CH₃), 1.06 (3H, s,4a-CH₃), 1.14 (3H, d, J=7.0 Hz, 5-CH₃), 1.31 (3H, t, J=7.3 Hz, S--CH₂CH₃), 1.54 (2H, seq, J=7.1 Hz, OCONHCH₂ CH₂ CH₃), 1.87 (3H, d, J=1.6 Hz,3-CH₃), 2.13 (1H, br d, J=16.3 Hz, 4-H), 2.34 (1H, dq, J=7.0, 2.2 Hz,5-H), 2.77 (1H, dq, J=12.8, 7.3 Hz, S--CH₂ CH₃), 2.81 (1H, d, J=16.3 Hz,4-H), 2.87 (1H, dq, J=12.8, 7.3 Hz, S--CH₂ CH₃), 3.09 (3H, s, N--CH₃),3.15 (2H, br dt, J=7.1 Hz, OCONHCH₂ CH₂ CH₃), 3.57 (1H, br d, J=5.3 Hz,7-H), 4.82 (1H, m, NH), 4.96 (1H, m, 6-H), 5.70 (1H, d, J=5.3 Hz, 8-H),5.71 (1H, s, 9-H); MS (FAB) m/z 405 (M+H)⁺.

Example 108

(4aR,5R,6R,7R)-7-Ethylthio-6-(pyrrolidin-1-ylcarbonyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (45m(=0.11 mmol) prepared in Example 106 was dissolved in toluene (1 ml),pyrrolidine (45 μl=0.54 mmol) was added to the solution, and the mixturewas stirred at room temperature for 1 hr, followed by purification bypreparative TLC to give the title compound (41 mg, 92%).

¹ H NMR (CDCl₃) δ 1.12 (3H, s, 4a-CH₃), 1.15 (3H, d, J=7.1 Hz, 5-CH₃),1.30 (3H, t, J=7.4 Hz, S--CH₂ CH₃), 1.82-1.89 (4H, m, OCOC₄ H₈ N), 1.87(3H, d, J=1.5 Hz, 3-CH₃), 2.14 (1H, br d, J=15.9 Hz, 4-H), 2.36 (1H, dq,J=7.1, 2.5 Hz, 5-H), 2.80 (1H, dq, J=12.6, 7.4 Hz, S--CH₂ CH₃), 2.82(1H, d, J=15.9 Hz, 4-H), 2.91 (1H, dq, J=12.6, 7.4 Hz, S--CH₂ CH₃), 3.10(3H, s, N--CH₃), 3.28 (2H, br t, J=6.7 Hz, OCOC₄ H₈ N), 3.39 (2H, br t,J=5.6 Hz, OCOC₄ H₈ N), 3.63 (1H, br d, J=5.2 Hz, 7-H), 4.94 (1H, m,6-H), 5.69 (1H, d, J=5.2 Hz, 8-H), 5.71 (1H, s, 9-H); MS (FAB) m/z 417(M+H)⁺.

Example 109

(4aR,5R,6R,7R)-6-Hydroxy-7-phenylthio-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz [f]indol-2(4H)-one

The procedure of Example 2 was repeated, except that the compound (37mg=0.12 mmol) prepared in Example 96 was dissolved in methylene chloride(0.8 ml), methanesulfonic acid (3 μl=0.05 mmol) was added to thesolution in the presence of thiophenol (24 μl=0.23 mmol), and themixture was stirred at room temperature for 15 min, followed bypurification by preparative TLC to give the title compound (34 mg, 81%).

¹ H NMR (CDCl₃) δ 1.15 (3H, s, 4a-CH₃), 1.18 (3H, d, J=7.3 Hz, 5-CH₃),1.87 (3H, d, J=2.0 Hz, 3-CH₃), 2.08 (1H, br d, J=15.9 Hz, 4-H), 2.15(1H, dq, J=7.3, 2.2 Hz, 5-H), 2.79 (1H, d, J=15.9 Hz, 4-H), 3.10 (3H, s,N--CH₃), 3.99 (1H, m, 6-H), 4.02 (1H, br d, J=4.9 Hz, 7-H), 5.77 (1H, s,9-H), 5.81 (1H, d, J=4.9 Hz, 8-H), 7.21-7.33 (3H, m, S--C₆ H₅),7.39-7.43 (2H, m, S--C₆ H₅); MS (FAB) m/z 368 (M+H)⁺.

Example 110

(4aR,5R,6R,7R)-7-Fhenylthio-6-propionyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of 3 was repeated, except that the compound (22 mg=0.06mmol) prepared in Example 109 was dissolved in methylene chloride (0.5ml), propionyl chloride (24 μl=0.28 mmol) was added to the solution inthe presence of pyridine (50 μl=0.62 mmol), and the mixture was stirredat room temperature for 70 hr. Thus, the title compound (18 mg, 69%) wasprepared.

¹ H NMR (CDCl₃) δ 1.07 (3H, d, J=7.2 Hz, 5-CH₃), 1.12 (3H, s, 4a-CH₃),1.13 (3H, t, J=7.5 Hz, OCOCH₂ CH₃), 1.88 (3H, d, J=1.9 Hz, 3-CH₃), 2.07(1H, br d, J=15.9 Hz, 4-H), 2.29 (1H, dq, J=7.2, 2.2 Hz, 5-H), 2.32 (2H,q, J=7.5 Hz, OCOCH₂ CH₃), 2.80 (1H, d, J=15.9 Hz, 4-H), 3.12 (3H, s,N--CH₃), 3.93 (1H, dd, J=5.0, 1.5 Hz, 7-H), 5.19 (1H, m, 6-H), 5.76 (1H,s, 9-H), 5.78 (1H, d, J=5.0 Hz, 8-H), 7.24-7.36 (3H, m, S--C₆ H₅),7.49-7.53 (2H, m, S--C₆ H₅); MS (FAB) m/z 424 (M+H)⁺.

Example 111

(4aR, 5R)-6-Oxo-4a, 5,6,7-tetrahydro-1, 3, 4a, 5-tetramethylbenz[f]indol-2 (4H )-one

The compound (20 mg=0.07 mmol) prepared in Example 24 was dissolved inbenzene (4 ml), methanesulfonic acid (4.5 μl=0.07 mmol) was added to thesolution, and the mixture was heated at 60° under reflux for 20 min. Thereaction mixture was cooled, benzene was added thereto, the mixture waswashed with saturated saline, and the organic phase was dried oversodium sulfate. The solvent was removed under reduced pressure, and theresidue was purified by preparative TLC to give the title compound (6mg, 36%).

¹ H NMR (CDCl₃) δ 0.90 (3H, s, 4a-CH₃), 1.15 (3H, d, J=6.7 Hz, 5-CH₃),1.91 (3H, d, J=2.2 Hz, 3-CH₃), 2.45 (1H, br d, J=15.9 Hz, 4-H), 2.77(1H,d, J=15.9 Hz, 4-H), 2.82 (1H, q, J=6.7 Hz, 5-H), 3.01 (1H, dd, J=23.3,4.1 Hz, 7-H), 3.14 (3H, s, N--CH₃), 3.17 (1H, dd, J=23.3, 4.1 Hz, 7-H),5.77 (1H, br t, J=4.1 Hz, 8-H), 5.79 (1H, s, 9-H); MS (EI) m/z 257 (M)⁺.

Example 112

(4aR,5R,6S)-6-Hydroxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The compound (215 mg=0.84 mmol) prepared in Example 111 was dissolved inmethanol (4 ml), sodium borohydride (63 mg=1.67 mmol) was added to thesolution, the mixture was stirred at room temperature for 30 min. Waterwas added to the reaction mixture, and the solvent was removed underreduced pressure. The residue was purified by preparative TLC to givethe title compound (190 mg, 88%).

¹ H NMR (CDCl₃) δ 1.14 (3H, s, 4a-CH₃), 1.18 (3H, d, J=7.0 Hz, 5-CH₃),1.74 (1H, dq, J=7.0, 2.7 Hz, 5-H), 1.85 (3H, d, J=2.0 Hz, 3-CH₃), 2.09(1H, br d, J=16.0 Hz, 4-H), 2.40 (1H, br dd, J=20.5, 4.2 Hz, 7-H), 2.58(1H, br ddd, J=20.5, 4.2 Hz, 7-H), 2.71 (1H, d, J=16.0 Hz, 4-H), 3.09(3H, s, N--CH₃), 4.01 (1H, m, 6-H), 5.68 (1H, br t, J=4.2 Hz, 8-H), 5.74(1H, s, 9-H); MS (EI) m/z 259 (M)⁺.

Example 113

(4aR,5R,6S)-6-Propionyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 3 was repeated, except that the compound (20mg=0.08 mmol) prepared in Example 112 was dissolved in pyridine (0.4ml), propionyl chloride (14 μl=0.22 mmol) was added to the solution, andthe mixture was stirred at room temperature for 12 hr. Thus, the titlecompound (14 mg, 58%) was prepared.

¹ H NMR (CDCl₃) δ 1.07 (3H, d, J=7.0 Hz, 5-CH₃), 1.11 (3H, t, J=7.5 Hz,OCOCH₂ CH₃), 1.13 (3H, s, 4a-CH₃), 1.87 (3H, d, J=2.0 Hz, 3-CH₃), 1.88(1H, dq, J=7.0, 2.7 Hz, 5-H), 2.11 (1H, br d, J=16.0 Hz, 4-H), 2.31 (2H,q, J=7.5 Hz, OCOCH₂ CH₃), 2.52 (1H, br dd, J=20.5, 4.2 Hz, 7-H), 2.72(1H, br ddd, J=20.5, 4.2 Hz, 7-H), 2.78 (1H, d, J=16.0 Hz, 4-H), 3.09(3H, s, N--CH₃), 5.13 (1H, m, 6-H), 5.63 (1H, br t, J=4.2 Hz, 8-H), 5.73(1H, s, 9-H); MS (EI) m/z 315 (M)⁺.

Example 114

(4aR,5R,6S)-6-Benzoyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 3 was repeated, except that the compound (18mg=0.07 mmol) prepared in Example 112 was dissolved in pyridine (0.4ml), benzoyl chloride (16 μl=0.14 mmol) was added to the solution, andthe mixture was stirred at room temperature for 12 hr. Thus, the titlecompound (14 mg, 56%) was prepared.

¹ H NMR (CDCl₃) δ 1.15 (3H, d, J=7.0 Hz, 5-CH₃), 1.27 (3H, s, 4a-CH₃),1.88 (3H, d, J=2.0 Hz, 3-CH₃), 2.02 (1H, dq, J=7.0, 2.7 Hz, 5-H), 2.18(1H, br d, J=16.0 Hz, 4-H), 2.52 (1H, br dd, J=20.5, 4.2 Hz, 7-H), 2.72(1H, br ddd, J=20.5, 4.2 Hz, 7-H), 2.84 (1H, d, J=16.0 Hz, 4-H), 3.11(3H, s, N--CH₃), 5.40 (1H, m, 6-H), 5.68 (1H, br t, J=4.2 Hz, 8-H), 5.76(1H, s, 9-H), 7.40-8.10 (5H, m, OCOC₆ H₅); MS (EI) m/z 363 (M)⁺.

Example 115

(4aR,5R,6S)-6-(Imidazol-1-ylcarbonyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 5 was repeated, except that the compound (101mg=0.39 mmol) prepared in Example 112 was dissolved in methylenechloride (2 ml), 1,1'-carbonyldiimidazole (143 mg=0.88 mmol) was addedto the solution, and the mixture was stirred at room temperature for 3hr. Thus, the title compound (130 mg, 95%) was prepared.

¹ H NMR (CDCl₃) δ 1.21 (3H, d, J=7.0 Hz, 5-CH₃), 1.21 (3H, s, 4a-CH₃),1.91 (3H, d, J=2.0 Hz, 3-CH₃), 2.08 (1H, dq, J=7.0, 2.6 Hz, 5-H), 2.20(1H, br d, J=16.1 Hz, 4-H), 2.62 (1H, br dd, J=20.6, 4.7 Hz, 7-H), 2.79(1H, br ddd, J=20.6, 4.7, 3.7 Hz, 7-H), 2.86 (1H, d, J=16.1 Hz, 4-H),3.14 (3H, s, N--CH₃), 5.38 (1H, m, 6-H), 5.66 (1H, br t, J=3.7 Hz, 8-H),5.76 (1H, s, 9-H), 7.09 (1H, br s, OCOC₃ H₃ N₂), 7.41 (1H, br s, OCOC₃H₃ N₂), 8.12 (1H, br s, OCOC₃ H₃ N₂); MS (EI) m/z 353 (M)⁺.

Example 116

(4aR,5R,6S)-6-Propylcarbamoyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (40mg=0.11 mmol) prepared in Example 115 was dissolved in toluene (0.8 ml),propylamine (94 μl=1.14 mmol) was added to the solution, and the mixturewas stirred at room temperature for 2 hr and then at 50° C. for 2 hr,followed by purification by preparative TLC to give the title compound(35 mg, 89%).

¹ H NMR (CDCl₃) δ 0.91 (3H, t, J=7.1 Hz, OCONHCH₂ CH₂ CH₃), 1.03 (3H, s,4a-CH₃), 1.09 (3H, d, J=6.9 Hz, 5-CH₃), 1.53 (2H, seq, J=7.1 Hz,OCONHCH₂ CH₂ CH₃), 1.83 (1H, br q, J=6.9 Hz, 5-H), 1.85 (3H, br s,3-CH₃), 2.10 (1H, br d, J=16.0 Hz, 4-H), 2.45 (1H, dd, J=20.4, 4.5 Hz,7-H), 2.56 (1H, br ddd, J=20.4, 4.5 Hz, 7-H), 2.77 (1H, d, J=16.0 Hz,4-H), 3.08 (3H, s, N--CH₃), 3.14 (2H, br dt, J=7 Hz, OCONHCH₂ CH₂ CH₃),4.99 (1H, m, NH), 5.04 (1H, m, 6-H), 5.65 (1H, m, 8-H), 5.71 (1H, s,9-H); MS (FAB) m/z 343 (M-H)⁺.

Example 117

(4aR,5R,6S)-6-(Pyrrolidin-1-ylcarbonyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one

The procedure of Example 6 was repeated, except that the compound (40mg=0.11 mmol) prepared in Example 115 was dissolved in toluene (0.8 ml),pyrrolidine (47 μl=0.56 mmol) was added to the solution, and the mixturewas stirred at room temperature for 1 hr, followed by purification bypreparative TLC to give the title compound (36 mg, 89%).

¹ H NMR (CDCl₃) δ 1.11 (3H, d, J=7.2 Hz, 5-CH₃), 1.12 (3H, s, 4a-CH₃),1.79-1.89 (4H, m, OCOC₄ H₈ N), 1.86 (3H, d, J=1.9 Hz, 3-CH₃), 1.89 (1H,dq, J=7.2, 2.7 Hz, 5-H), 2.12 (1H, br d, J=15.9 Hz, 4-H), 2.47 (1H, dd,J=20.5, 4.9 Hz, 7-H), 2.59 (1H, br ddd, J=20.5, 4.9 Hz, 7-H), 2.79 (1H,d, J=5.9 Hz, 4-H), 3.10 (3H, s, N--CH₃), 3.28 (2H, br t, J=6.7 Hz, OCOC₄H₈ N), 3.38 (2H, br t, J=5.9 Hz, OCOC₄ H₈ N), 5.01 (1H, m, 6-H), 5.65(1H, m, 8-H), 5.73 (1H, s, 9-H); MS (FAB) m/z 355 (M-H)⁺.

Example 118

(4aR,5R,6R,7S)-6,7-Dihydroxy-1-ethyl-4a,5,6,7-tetrahydro-3,4a,5-trimethylbenz[f]indol-2(4H)-one

A compound (300 mg=1.15 mmol) represented by the formula (III) wasdissolved in methylene chloride (6 ml), and the solution was cooled to-15° C. Methanesulfonyl chloride (133 μl=1.73 mmol) was added to thesolution in the presence of diisopropylethylamine (399 μl=2.29 mmol),and the mixture was stirred for 15 min. Methylene chloride (60 ml) wasadded to the reaction mixture, the mixture was washed with saturatedsaline (60 ml), and the solvent was removed under reduced pressure. A 2M ethylamine/THF solution (3.5 ml) was added to the residue, and themixture was stirred at room temperature for 24 hr. The solvent wasremoved under reduced pressure, the reaction product was dissolved inacetonitrile (15 ml), acetic acid (720 μl=12.0 mmol) was added to thesolution, and the mixture was stirred at room temperature for 24 hr.Methylene chloride (60 ml) was added to the reaction mixture, themixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (60 ml×2) and saturated saline (60 ml), and the organic phasewas dried over sodium sulfate. The residue was purified by preparativeTLC to give the title compound (170 mg, 51%).

¹ H NMR (CDCl₃) δ 1.14 (3H, t, J=7.4 Hz, N--CH₂ CH₃ ), 1.15 (3H, s,4a-CH₃), 1.20 (3H, d, J=7.1 Hz, 5-CH₃), 1.75 (1H, dq, J=7.1, 1.7 Hz,5-H), 1.83 (3H, d, J=1.7 Hz, 3-CH₃), 2.06 (1H, br d, J=15.9 Hz, 4-H),2.76 (1H, d, J=15.9 Hz, 4-H), 3.59 (2H, m, N--CH₂ CH₃), 3.89 (1H, m,6-H), 4.36 (1H, m, 7-H), 5.72 (1H, s, 9-H), 5.57 (1H, s, 8-H); MS(EI)m/z 289 (M)⁺ ; [α]²⁰ _(D) -140° (c 1.0, MeOH).

Example 119

(4aR,5R,6R,7R)-1-Ethyl-6-hydroxy-7-methoxy-4a,5,6,7-tetrahydro-3,4a,5-trimethylbenz[f]indol-2(4H)-one

A compound (300 mg=1.15 mmol) represented by the formula (III) wasdissolved in methylene chloride (6 ml), and the solution was cooled to-15° C. Methanesulfonyl chloride (133 μl=1.73 mmol) was added to thereaction mixture in the presence of diisopropylethylamine(399 μl=2.29mmol), and the mixture was stirred for 15 min. Methylene chloride (60ml) was added to the reaction mixture, the mixture was washed withsaturated saline (60 ml), and the solvent was removed under reducedpressure. A 2 M ethylamine/THF solution (3.5 ml) was added to theresidue, and the mixture was stirred at room temperature for 24 hr. Thesolvent was removed under reduced pressure, and the reaction product wasdissolved in acetonitrile (15 ml), acetic acid (720 μl=12.0 mmol) wasadded to the solution, and the mixture was stirred at room temperaturefor 24 hr. Methylene chloride (60 ml) was added to the reaction mixture,the mixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (60 ml×2) and saturated saline (60 ml), and the organic phasewas dried over sodium sulfate. The solvent was removed under reducedpressure, methanol (30 ml) was added to the reaction product, and themixture was stirred at 50° C. for 3 hr. The solvent was removed underreduced pressure, and the residue was purified by preparative TLC togive the title compound (100 mg, 29%).

¹ H NMR (CDCl₃) δ 1.10 (3H, 5, 4a-CH₃), 1.16 (3H, t, J=7.2 Hz, N--CH₂CH₃ ), 1.17 (3H, d, J=7.3 Hz, 5-CH₃), 1.84 (3H, d, J=1.9 Hz, 3-CH₃),1.90 (1H, dq, J=7.3, 2.7 Hz, 5-H), 2.12 (1H, br d, J=15.9 Hz, 4-H), 2.77(1H, d, J=15.9 Hz, 4-H), 3.42 (3H, s, O--CH₃), 3.57 (1H, dq, J=7.1, 7.2Hz, N--CH₂ CH₃), 3.62 (1H, dq, J=7.1, 7.2 Hz, N--CH₂ CH₃ ), 3.70 (1H,dd, J=4.8, 1.7 Hz, 7-H), 3.90 (1H, br s, 6-H), 5.75 (1H, s, 9-H), 5.80(1H, d, J=4.8 Hz, 8-H); MS (EI) m/z 303 (M)⁺ ; [α]¹⁸ _(D) -414° (c 1.0,MeOH); mp 151-154° C.

Example 120

(4aR,5R,6R,7R)-1-Ethyl-7-methoxy-6-propionyloxy-4a,5,6,7-tetrahydro-3,4a,5-trimethylbenz[f]indol-2(4H)-one

The compound (34 mg=0.11 mmol) prepared in Example 119 was dissolved inpyridine (1 ml), propionyl chloride (34 μl=0.55 mmol) was added to thesolution, and the mixture was stirred at room temperature for 24 hr.Methylene chloride (20 ml) was added to the reaction mixture, themixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (20 ml×2) and saturated saline (20 ml), and the solvent wasremoved under reduced pressure. The organic phase was dried over sodiumsulfate, and the solvent was removed under reduced pressure. The residuewas purified by preparative TLC to give the title compound (12 mg, 30%).

¹ H NMR (CDCl₃) δ 1.08 (3H, d, J=7.3 Hz, 5-CH₃), 1.09 (3H, s, 4a-CH₃),1.14 (3H, t, J=7.5 Hz, OCOCH₂ CH₃ ), 1.15 (3H, t, J=7.2 Hz, N--CH₂ CH₃), 1.86 (3H, d, J=1.9 Hz, 3-CH₃), 2.08 (1H, dq, J=7.3, 2.7 Hz, 5-H),2.14 (1H, br d, J=15.9 Hz, 4-H), 2.34 (2H, q, J=7.5 Hz, OCOCH₂ CH₃),2.80 (1H, d, J=15.9 Hz, 4-H), 3.50 (3H, s, O--CH₃), 3.60 (1H, dd, J=4.8,1.7 Hz, 7-H), 3.61 (2H, m, N--CH₂ CH₃), 5.09 (1H, m, 6-H), 5.73 (1H, s,9-H), 5.74 (1H, d, J=4.8 Hz, 8-H); MS (EI) m/z 359 (M)⁺ ; [α]¹⁸ _(D)-228° (c 1.0, MeOH).

Example 121

(4aR,5R,6R,7R)-1-Ethyl-6-(2-furancarbonyloxy)-7-methoxy-4a,5,6,7-tetrahydro-3,4a,5-trimethylbenz[f]indol-2(4H)-one

The compound (28 mg=0.09 mmol) prepared in Example 119 was dissolved inpyridine (1 ml), 2-furoyl chloride (27 μl=0.27 mmol) was added to thesolution, and the mixture was stirred at room temperature for 24 hr.Methylene chloride (20 ml) was added to the reaction mixture, themixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (20 ml×2) and saturated saline (20 ml), and the solvent wasremoved under reduced pressure. The organic phase was dried over sodiumsulfate, and the solvent was removed under reduced pressure. The residuewas purified by preparative TLC to give the title compound (31 mg, 85%).

¹ H NMR (CDCl₃) δ 1.15 (3H, d, J=7.3 Hz, 5-CH₃), 1.16 (3H, t, J=7.2 Hz,N--CH₂ CH₃ ), 1.87 (3H, d, J=1.9 Hz, 3-CH₃), 1.21 (3H, s, 4a-CH₃), 2.17(1H, dq, J=7.3, 2.7 Hz, 5-H), 2.18 (1H, br d, J=15.9 Hz, 4-H), 2.83 (1H,d, J=15.9 Hz, 4-H), 3.55 (3H, s, O--CH₃), 3.59 (1H, dq, J=7.0, 7.2 Hz,N--CH₂ CH₃), 3.66 (1H, dq, J=7.0, 7.2 Hz, N--CH₂ CH₃), 3.73 (1H, br d,J=4.8 Hz, 7-H), 5.29 (1H, br s, 6-H), 5.75 (1H, s, 9-H), 5.76 (1H, d,J=4.8 Hz, 8-H), 6.49 (1H, dd, J=3.5, 1.7 Hz, OCOC₄ H₃ O), 7.11 (1H, dd,J=3.5, 0.8 Hz, OCOC₄ H₃ O), 7.57 (1H, dd, J=1.7, 0.8 Hz, OCOC⁺ ; OCOC₄H₃ O); MS (EI) m/z 397 (M)⁺ ; [α]¹⁸ _(D) -17° (c 1.0, MeOH).

Example 122

(4aR, 5R, 6R, 7R)-1-Benzyl-6-hydroxy-7-methoxy-4a,5,6,7-tetrahydro-3,4a,5-trimethylbenz[f]indol-2(4H)-one

A compound (70 mg=0.27 mmol) represented by the formula (III) wasdissolved in methylene chloride (1.4 ml), and the solution was cooled to-15° C. Methanesulfonyl chloride (31 μl=0.40 mmol) was added to thereaction mixture in the presence of diisopropylethylamine (93 μl=0.53mmol), and the mixture was stirred for 15 min. Methylene chloride (10ml) was added to the reaction mixture, the mixture was washed withsaturated saline (10 ml), and the solvent was removed under reducedpressure. A 2 M benzylamine/THF solution (267 μl) was added to theresidue, and the mixture was stirred at room temperature for 4 hr. Thesolvent was removed under reduced pressure, and the reaction product wasdissolved in acetonitrile (3.5 ml), acetic acid (160 μl=2.7 mmol) wasadded to the solution, and the mixture was stirred at room temperaturefor 20 hr. Methylene chloride (10 ml) was added to the reaction mixture,the mixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (10 ml×2) and saturated saline (10 ml), and the organic phasewas dried over sodium sulfate. The solvent was removed under reducedpressure, methanol (7 ml) was added to the reaction product, and themixture was stirred at 60° C. for 5 hr. The solvent was removed underreduced pressure, and the residue was purified by preparative TLC togive the title compound (9 mg, 9%).

¹ H NMR (CDCl₃) δ 1.08 (3H, s, 4a-CH₃), 1.17 (3H, d, J=7.4 Hz, 5-CH₃),1.88 (1H, dq, J=7.4, 2.5 Hz, 5-H), 1.91 (3H, d, J=1.8 Hz, 3-CH₃), 2.14(1H, br d, J=15.9 Hz, 4-H), 2.79 (1H, d, J=15.9 Hz, 4-H), 3.38 (3H, s,O--CH₃), 3.64 (1H, dd, J=4.8, 1.9 Hz, 7-H), 3.88 (1H, br s, 6-H), 4.69(1H, d, J=15.9 Hz, N--CH₂ C₆ H₅), 4.87 (1H, d, J=15.9 Hz, N--CH₂ C₆ H₅),5.64 (1H, s, 9-H), 5.70 (1H, d, J=4.8 Hz, 8-H), 7.16-7.30 (5H, m, N--CH₂C₆ H₅ ); MS (EI)m/z 365 (M)⁺ ; [α]²⁰ _(D) -354° (c 1.0, MeOH); mp 45° C.

Example 123

(4aR,5R,6R,7R)-1-Benzyl-6-(2-furancarbonyloxy)-7-methoxy-4a,5,6,7-tetrahydro-3,4a,5-trimethylbenz[f]indol-2(4H)-one

The compound (23 mg=0.06 mmol) prepared in Example 122 was dissolved inpyridine (1 ml), 2-furoyl chloride (19 μl=0.19 mmol) was added to thesolution, and the mixture was stirred at room temperature for 16 hr.Methylene chloride (20 ml) was added to the reaction mixture, themixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (20 ml×2) and saturated saline (20 ml), and the solvent wasremoved under reduced pressure. The organic phase was dried over sodiumsulfate, and the solvent was removed under reduced pressure. The residuewas purified by preparative TLC to give the title compound (30 mg,100%).

¹ H NMR (CDCl₃) δ 1.14 (3H, d, J=7.1 Hz, 5-CH₃), 1.19 (3H, s, 4a-CH₃),1.93 (3H, d, J=1.8 Hz, 3-CH₃), 2.14 (1H, dq, J=7.1, 2.8 Hz, 5-H), 2.19(1H, br d, J=15.9 Hz, 4-H), 2.85 (1H, d, J=15.9 Hz, 4-H), 3.52 (3H, s,O--CH₃), 3.68 (1H, dd, J=4.7, 1.1 Hz, 7-H), 4.69 (1H, d, J=15.9 Hz,N--CH₂ C₆ H₅), 4.91 (1H, d, J=15.9 Hz, N--CH₂ C₆ H₅), 5.27 (1H, m, 6-H),5.65 (1H, s, 9-H), 5.66 (1H, d, J=4.8 Hz, 8-H), 6.49 (1H, dd, J=3.5, 1.7Hz, OCOC₄ H₃ O), 7.09 (1H, dd, J=3.5, 0.8 Hz, OCOC₄ H₃ O), 7.17-7.32(5H, m, N--CH₂ C₆ H₅ ), 7.56 (1H, dd, J=1.7, 0.8 Hz, OCOC₄ H₃ O); MS(EI)m/z 459 (M)⁺ ; [α]²⁰ _(D) -30° (c 1.0, MeOH).

Example 124

(4aR,5R,6R,7R)-6-Hydroxy-7-methoxy-1-(4-methoxybenzyl)-4a,5,6,7-tetrahydro-3,4a,5-trimethylbenz[f]indol-2(4H)-one

A compound (100 mg=0.38 mmol) represented by the formula (III) wasdissolved in methylene chloride (2 ml), and the solution was cooled to-15° C. Methanesulfonyl chloride (44 μl=0.57 mmol) was added to thereaction mixture in the presence of diisopropylethylamine (133 μl=0.76mmol), and the mixture was stirred for 15 min. Methylene chloride (10ml) was added thereto, the mixture was washed with saturated saline (10ml), and the solvent was removed under reduced pressure. A 2 M4-methoxybenzylamine/THF solution (955 μl) was added to the residue, andthe mixture was stirred at room temperature for 5 hr. The solvent wasremoved under reduced pressure, the reaction product was dissolved inacetonitrile (5 ml), acetic acid (230 μl=3.79 mmol) was added to thereaction solution, and the mixture was stirred at room temperature for16 hr. Methylene chloride (10 ml) was added to the reaction mixture, themixture was washed with a saturated aqueous sodium hydrogencarbonatesolution (10 ml×2) and saturated saline (10 ml), and the organic phasewas dried over sodium sulfate. The solvent was removed under reducedpressure, and methanol (10 ml) was added to the reaction product, andthe mixture was stirred at 50° C. for 5 hr. The solvent was removedunder reduced pressure, and the residue was purified by preparative TLCto give the title compound (30 mg, 20%).

¹ H NMR (CDCl₃) δ 1.07 (3H, s, 4a-CH₃), 1.17 (3H, d, J=7.3 Hz, 5-CH₃),1.87 (1H, dq, J=7.3, 2.5 Hz, 5-H), 1.89 (3H, d, J=1.7 Hz, 3-CH₃), 2.12(1H, br d, J=15.9 Hz, 4-H), 2.78 (1H d, J=15.9 Hz, 4-H), 3.39 (3H, s,O--CH₃), 3.65 (1H, dd, J=4.7, 1.7 Hz, 7-H), 3.76 (3H, s, N--CH₂ C₆ H₄OCH₃ ), 3.88 (1H, br s, 6-H), 4.62 (1H, d, J=15.7 Hz, N--CH₂ C₆ H₄OCH₃), 4.80 (1H, d, J=15.7 Hz, N--CH₂ C₆ H₄ OCH₃), 5.66 (1H, s, 9-H),5.71 (1H, d, J=4.7 Hz, 8-H), 6.80 (2H, d, J=8.8 Hz, N--CH₂ C₆ H₄ OCH₃),7.11 (2H, d, J=8.8 Hz, N--CH₂ C₆ H₄ OCH₃); MS (FAB) m/z 396 (M+H)⁺ ;[α]²⁰ _(D) -175° (c 1.0, MeOH).

The structures of the respective compounds prepared in the aboveexamples are summarized below.

    __________________________________________________________________________    R.sup.1              R.sup.2            R.sup.3                               __________________________________________________________________________     2 CH.sub.3 --       H                  CH.sub.3 CO--O--                       3                                                                                ##STR8##         CH.sub.3 CH.sub.2 CO--                                                                            ##STR9##                              4                                                                                ##STR10##                                                                                       ##STR11##                                                                                        ##STR12##                             5                                                                                ##STR13##                                                                                       ##STR14##                                                                                        ##STR15##                             6                                                                                ##STR16##                                                                                       ##STR17##                                                                                        ##STR18##                             7                                                                                ##STR19##        H                  CH.sub.3 CH.sub.2 CO--O--              8                                                                                ##STR20##        CH.sub.3 CH.sub.2 CO--                                                                            ##STR21##                             9                                                                                ##STR22##                                                                                       ##STR23##                                                                                        ##STR24##                            10                                                                                ##STR25##        H                  HO--                                  11                                                                                ##STR26##        H                  (CH.sub.3).sub.3 C--Si(CH.sub.3).s                                            ub.2 --O--                            12                                                                                ##STR27##        CH.sub.3 CO--      HO--                                  13 CH.sub.3 --       CH.sub.3 CH.sub.2 CO--                                                                           HO--                                  14                                                                                ##STR28##                                                                                       ##STR29##                                                                                        ##STR30##                            15                                                                                ##STR31##                                                                                       ##STR32##                                                                                        ##STR33##                            16                                                                                ##STR34##                                                                                       ##STR35##                                                                                        ##STR36##                            17                                                                                ##STR37##                                                                                       ##STR38##                                                                                        ##STR39##                            18                                                                                ##STR40##        CH.sub.3 (CH.sub.2).sub.3 --                                                                      ##STR41##                            19                                                                                ##STR42##        (CH.sub.3).sub.2 CH(CH.sub.2).sub.2 --                                                            ##STR43##                            20                                                                                ##STR44##                                                                                       ##STR45##                                                                                        ##STR46##                            21                                                                                ##STR47##        CH.sub.2 ═CH--CH.sub.2 --                                                                     ##STR48##                            22                                                                                ##STR49##        CH.sub.3 (CH.sub.2).sub.2 --NH--CO--                                                              ##STR50##                            23                                                                                ##STR51##                                                                                       ##STR52##                                                                                        ##STR53##                            24 CH.sub.3 --       H                  CH.sub.3 --O--                        25                                                                                ##STR54##        CH.sub.3 CO--                                                                                     ##STR55##                            26                                                                                ##STR56##        CH.sub.3 CH.sub.2 CO--                                                                            ##STR57##                            27                                                                                ##STR58##                                                                                       ##STR59##                                                                                        ##STR60##                            28                                                                                ##STR61##                                                                                       ##STR62##                                                                                        ##STR63##                            29                                                                                ##STR64##                                                                                       ##STR65##                                                                                        ##STR66##                            30                                                                                ##STR67##                                                                                       ##STR68##                                                                                        ##STR69##                            31                                                                                ##STR70##                                                                                       ##STR71##                                                                                        ##STR72##                            32                                                                                ##STR73##                                                                                       ##STR74##                                                                                        ##STR75##                            33                                                                                ##STR76##                                                                                       ##STR77##                                                                                        ##STR78##                            34                                                                                ##STR79##        CH.sub.3 --                                                                                       ##STR80##                            35 CH.sub.3 --       CH.sub.3 CH.sub.2 --                                                                             CH.sub.3 --O--                        36                                                                                ##STR81##        CH.sub.3 (CH.sub.2).sub.2 --                                                                      ##STR82##                            37                                                                                ##STR83##        CH.sub.3 (CH.sub.2).sub.3 --                                                                      ##STR84##                            38                                                                                ##STR85##        (CH.sub.3).sub.2 CH(CH.sub.2).sub.2 --                                                            ##STR86##                            39                                                                                ##STR87##        CH.sub.3 CH.sub.2 (CH.sub.3)CHCH.sub.2 --                                                         ##STR88##                            40                                                                                ##STR89##                                                                                       ##STR90##                                                                                        ##STR91##                            41                                                                                ##STR92##        CH.sub.2 ═CH--CH.sub.2 --                                                                     ##STR93##                            42                                                                                ##STR94##                                                                                       ##STR95##                                                                                        ##STR96##                            43                                                                                ##STR97##                                                                                       ##STR98##                                                                                        ##STR99##                            44                                                                                ##STR100##                                                                                      ##STR101##                                                                                       ##STR102##                           45                                                                                ##STR103##       (HO).sub.2 CHCH.sub.2 --                                                                          ##STR104##                           46 CH.sub.3 --       HO--(CH.sub.2).sub.2 --                                                                          CH.sub.3 --O--                        47                                                                                ##STR105##                                                                                      ##STR106##                                                                                       ##STR107##                           48                                                                                ##STR108##       H.sub.2 N--CO--                                                                                   ##STR109##                           49                                                                                ##STR110##       CH.sub.3 NH--CO--                                                                                 ##STR111##                           50                                                                                ##STR112##       C.sub.2 H.sub.5 NH--CO--                                                                          ##STR113##                           51                                                                                ##STR114##       CH.sub.3 (CH.sub.2).sub.2 NH--CO--                                                                ##STR115##                           52                                                                                ##STR116##       (CH.sub.3).sub.2 CHNH--CO--                                                                       ##STR117##                           53                                                                                ##STR118##       (CH.sub.3).sub.2 CHCH.sub.2 NH--CO--                                                              ##STR119##                           54                                                                                ##STR120##       CH.sub.3 (CH.sub.2).sub.5 NH--CO--                                                                ##STR121##                           55                                                                                ##STR122##                                                                                      ##STR123##                                                                                       ##STR124##                           56                                                                                ##STR125##                                                                                      ##STR126##                                                                                       ##STR127##                           57 CH.sub.3 --                                                                                      ##STR128##        CH.sub.3 --O--                        58                                                                                ##STR129##       HO--(CH.sub.2).sub.2 --NH--CO--                                                                   ##STR130##                           59                                                                                ##STR131##       (C.sub.2 H.sub.5).sub.2 N--CO--                                                                   ##STR132##                           60                                                                                ##STR133##                                                                                      ##STR134##                                                                                       ##STR135##                           61                                                                                ##STR136##                                                                                      ##STR137##                                                                                       ##STR138##                           62                                                                                ##STR139##                                                                                      ##STR140##                                                                                       ##STR141##                           63                                                                                ##STR142##                                                                                      ##STR143##                                                                                       ##STR144##                           64                                                                                ##STR145##                                                                                      ##STR146##                                                                                       ##STR147##                           65                                                                                ##STR148##       C.sub.2 H.sub.5 O--CO--                                                                           ##STR149##                           66                                                                                ##STR150##                                                                                      ##STR151##                                                                                       ##STR152##                           67                                                                                ##STR153##                                                                                      ##STR154##                                                                                       ##STR155##                           68 CH.sub.3 --                                                                                      ##STR156##        CH.sub.3 O--                          69                                                                                ##STR157##                                                                                      ##STR158##                                                                                       ##STR159##                           70                                                                                ##STR160##       H                  C.sub.2 H.sub.5 O--                   71                                                                                ##STR161##       CH.sub.3 CO--                                                                                     ##STR162##                           72                                                                                ##STR163##       C.sub.2 H.sub.5 CO--                                                                              ##STR164##                           73                                                                                ##STR165##                                                                                      ##STR166##                                                                                       ##STR167##                           74                                                                                ##STR168##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2 --                                                            ##STR169##                           75                                                                                ##STR170##                                                                                      ##STR171##                                                                                       ##STR172##                           76                                                                                ##STR173##       CH.sub.3 (CH.sub.2).sub.2 NH--CO--                                                                ##STR174##                           77                                                                                ##STR175##       H                  (CH.sub.3).sub.2 CH--O--              78                                                                                ##STR176##       C.sub.2 H.sub.5 CO--                                                                              ##STR177##                           79 CH.sub.3 --                                                                                      ##STR178##        (CH.sub.3).sub.2 CH--O--              80                                                                                ##STR179##                                                                                      ##STR180##                                                                                       ##STR181##                           81                                                                                ##STR182##                                                                                      ##STR183##                                                                                       ##STR184##                           82                                                                                ##STR185##       C.sub.2 H.sub.5 --                                                                                ##STR186##                           83                                                                                ##STR187##       CH.sub.3 (CH.sub.2).sub.2 --                                                                      ##STR188##                           84                                                                                ##STR189##       CH.sub.3 (CH.sub.2).sub.3 --                                                                      ##STR190##                           85                                                                                ##STR191##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2 --                                                            ##STR192##                           86                                                                                ##STR193##                                                                                      ##STR194##                                                                                       ##STR195##                           87                                                                                ##STR196##                                                                                      ##STR197##                                                                                       ##STR198##                           88                                                                                ##STR199##       CH.sub.3 NHCO--                                                                                   ##STR200##                           89                                                                                ##STR201##       CH.sub.3 (CH.sub.2).sub.2 NHCO--                                                                  ##STR202##                           90 CH.sub.3 --       H                  (CH.sub.3).sub.2 CHCH.sub.2                                                   --O--                                 91                                                                                ##STR203##                                                                                      ##STR204##                                                                                       ##STR205##                           92                                                                                ##STR206##       CH.sub.3 (CH.sub.2).sub.2 NHCO--                                                                  ##STR207##                           93                                                                                ##STR208##       H                                                                                                 ##STR209##                           94                                                                                ##STR210##                                                                                      ##STR211##                                                                                       ##STR212##                           95                                                                                ##STR213##       CH.sub.3 (CH.sub.2).sub.2 NHCO--                                                                  ##STR214##                           96                                                                                ##STR215##       H                  CH.sub.3 --S--                        97                                                                                ##STR216##       C.sub.2 H.sub.5 CO--                                                                              ##STR217##                           98                                                                                ##STR218##                                                                                      ##STR219##                                                                                       ##STR220##                           99                                                                                ##STR221##                                                                                      ##STR222##                                                                                       ##STR223##                           100                                                                               ##STR224##       H                  C.sub.2 H.sub.5 --S--                 101                                                                              CH.sub.3 --       C.sub.2 H.sub.5 CO--                                                                             C.sub.2 H.sub.5 --S--                 102                                                                               ##STR225##                                                                                      ##STR226##                                                                                       ##STR227##                           103                                                                               ##STR228##       CH.sub.3 (CH.sub.2).sub.3 --                                                                      ##STR229##                           104                                                                               ##STR230##       (CH.sub.3).sub.2 CH(CH.sub.2).sub.2 --                                                            ##STR231##                           105                                                                               ##STR232##                                                                                      ##STR233##                                                                                       ##STR234##                           106                                                                               ##STR235##                                                                                      ##STR236##                                                                                       ##STR237##                           107                                                                               ##STR238##       CH.sub.3 (CH.sub.2).sub.2 NHCO--                                                                  ##STR239##                           108                                                                               ##STR240##                                                                                      ##STR241##                                                                                       ##STR242##                           109                                                                               ##STR243##       H                                                                                                 ##STR244##                           110                                                                               ##STR245##       C.sub.2 H.sub.5 CO--                                                                              ##STR246##                           112                                                                              CH.sub.3 --       H                  H                                     113                                                                               ##STR247##       C.sub.2 H.sub.5 CO--                                                                             H                                     114                                                                               ##STR248##                                                                                      ##STR249##        H                                     115                                                                               ##STR250##                                                                                      ##STR251##        H                                     116                                                                               ##STR252##       CH.sub.3 (CH.sub.2).sub.2 NHCO--                                                                 H                                     117                                                                               ##STR253##                                                                                      ##STR254##        H                                     118                                                                              C.sub.2 H.sub.5 --                                                                              H                  HO--                                  119                                                                               ##STR255##       H                  CH.sub.3 O--                          120                                                                               ##STR256##       C.sub.2 H.sub.5 CO--                                                                              ##STR257##                           121                                                                               ##STR258##                                                                                      ##STR259##                                                                                       ##STR260##                           122                                                                               ##STR261##       H                  CH.sub.3 O--                          123                                                                               ##STR262##                                                                                      ##STR263##                                                                                       ##STR264##                           124                                                                               ##STR265##       H                                                                                                 ##STR266##                           __________________________________________________________________________

Preparation

Tablets

An intimate powder mixture of the compound prepared in Example 8,lactose, crosslinked polyvidone, and hydroxypropylmethyl cellulose wasprepared and wet-granulated by a conventional method, and magnesiumstearate in an amount of 0.5 mg/tablet was added thereto.

The resultant mixture was compressed by a conventional method to preparetablets. Each tablet had the following composition.

    ______________________________________                                        Compound of Example 8                                                                             5.0 mg                                                    Lactose             185 mg                                                    Crosslinked polyvidone                                                                            7.0 mg                                                    Hydroxypropylmethyl cellulose                                                                     2.5 mg                                                    Magnesium stearate  0.5 mg                                                                        200 mg                                                    ______________________________________                                    

Biological Activity

The progesterone receptor binding activity of the compounds of thepresent invention was measured in the following manner in accordancewith the method of H. Kondo et. al. (J. Antibiotics, Vol. 43, pp.1533-1542, 1990).

Uteri taken from hogs in 5 mM phosphate buffer were disrupted usingPolytron homogenizer, and the resulting solution was centrifuged(100,000×g, 30 min) to separate the supernatant, thereby preparing acytosol containing progesterone receptor. A given concentration of atest drug solution (10 μl) was added to a solution composed of 50 μl ofthe cylosol obtained just above (2-3 mg protein/ml) and 40 μl of asolution of [³ H]-progesterone as a ligand (3.84 TBq/mmol, 18.5 kBq/ml),and they were incubated in a test, tube for 60 min at 4° C. to effect areaction. Then, 100 μl of a 0.5% activated carbon solution was added tothe reaction solution, and the mixture was allowed to stand for 10 minand then centrifuged (2,000×g, 10 min). The radioactivity of thesupernatant was measured with a liquid scintillation counter.

Separately, the radioactivity was measured in the same manner asdescribed above, except that no test drug was added. Further, theradioactivity was measured in the same manner as described above, exceptthat 10 μl of Medroxyprogesterone Acetate (MPA) (10 μg/ml) was addedinstead of the test drug. The radioactivity with no test drug added wasdefined as the amount of total binding of [³ H]-progesterone to thecytosol, and the radioactivity with MPA added was defined as the amountof non-specific binding. The inhibition ratio was calculated from thesemeasured values by the following equation to determine the bindinginhibitory activity (IC₅₀).

Inhibition ratio (%)= ##EQU1##

The compounds prepared in Examples 3, 4, 25, 26, 31, 32, 34, 35, 36, 41,97, 99, 100, 101, 106, 107, 108, 113, 115, 116, and 117 and Mifepristone(RU38486) had the following inhibitory activity against progesteronereceptor binding.

                  TABLE 1                                                         ______________________________________                                        Inhibitory activity against progesterone                                      receptor binding                                                                              Inhibitory activity                                           Ex. No. of compound                                                                           (IC.sub.50) (nM)                                              ______________________________________                                         3              28                                                             4              32                                                            25              25                                                            26              17                                                            31              47                                                            32              27                                                            34              42                                                            35              36                                                            36              51                                                            41              44                                                            97              64                                                            99              66                                                            100             119                                                           101             164                                                           106             137                                                           107             156                                                           108             155                                                           113             99                                                            115             22                                                            116             19                                                            117             31                                                            RU38486         106                                                           ______________________________________                                    

Test on Toxicity upon Continuous Administration

A homogeneous suspension of the compound, according to the presentinvention, prepared in Example 8 in a 0.2% aqueous methyl cellulosesolution was subcutaneously administered to 16 week-old male SD rats(five rats). The dose of the compound prepared in Example 8 was 60mg/kg. All the rats remained survived without no special symptom.

Chemical Stability Test

In order to evaluate the chemical stability of the compound according tothe present invention, a test on comparison of the compound (a) preparedin Example 24 with3β-hydroxy-2α-methoxy-1(10),7(11),8-eremophilatrien-12,8-olide (b) (acompound prepared in WO 97/30040) which is a compound provided byreplacing the nitrogen atom in the compound (a) with an oxygen atom wasperformed. In this comparison test, a change of the compounds (a) and(b) with the elapse of time was traced.

The test was performed by the following method.

The compounds (a) and (b) (each 1.0 mg) were accurately weighed and eachdissolved in 2.0 ml of methanol to prepare methanol solutions. Anaqueous NaOH solution (2.0 ml), which had been previously accuratelyadjusted to pH 11.5, was added to each of the methanol solutions, andthe amount of the residual compounds (a) and (b) was traced with theelapse of time by liquid chromatography (data processing device:Shimadzu CHROMATOPAC C-R4A, detector: Shimadzu LC-6A, column: GL ScienceInertsil ODS 4.6×100 mm, mobile phase: a 2:1 solution mixture of abuffer, prepared by adding 1000 ml of deionized water to 770 ml ofammonium acetate and 175 ml of dipotassium phosphate and adjusting themixture to pH 6.5 by addition of phosphoric acid, and acetonitrile,detection wavelength: 323 nm for the compound (a) and 320 nm for thecompound (b), temperature: 25° C., flow rate: 1 ml/min). The initialamount (time 0)of the compounds (a) and (b) was presumed to be 100% todetermine the percentage of the residual compounds (a) and (b). Theresults were as shown in FIG. 1.

As is apparent from the results shown in FIG. 1, the novel mothernucleus according to the present invention has much better chemicalstability than compounds having a ligularenolide type sesquiterpenemother nucleus with a lactone ring structure in its molecule.

What is claimed is:
 1. A compound represented by the following formula(I) or a pharmaceutically acceptable salt thereof: ##STR267## wherein R¹representsa hydrogen atom, optionally substituted C₁ -C₁₀ alkyl,optionally substituted C₂ -C₁₀ alkenyl, optionally substituted C₂ -C₁₀alkynyl, optionally substituted C₃ -C₁₀ cycloalkyl, or optionallysubstituted C₇ -C₁₅ aralkyl; R² representsa hydrogen atom, optionallysubstituted C₁ -C₁₀ alkylcarbonyl, optionally substituted C₂ -C₁₀alkenylcarbonyl, optionally substituted C₂ -C₁₀ alkynylcarbonyl,optionally substituted C₃ -C₁₅ cycloalkylcarbonyl, optionallysubstituted C₇ -C₁₅ aralkylcarbonyl, optionally substituted C₇ -C₁₅aromatic acyl, optionally substituted C₂ -C₁₅ heteroaromatic acyl havingat least one hetero atom selected from the group consisting of nitrogen,oxygen, and sulfur atoms, optionally substituted C₃ -C₁₅ saturatedheterocyclic acyl having at least one hetero atom selected from thegroup consisting of nitrogen, oxygen, and sulfur atoms, optionallysubstituted C₁ -C₁₀ alkyl, optionally substituted C₂ -C₁₀ alkenyl,optionally substituted C₂ -C₁₀ alkynyl, optionally substituted C₃ -C₁₀cycloalkyl, optionally substituted C₇ -C₁₅ aralkyl, carbamoyl,optionally substituted N--C₁ -C₁₀ alkylcarbamoyl, optionally substitutedN--C₆ -C₁₅ aromatic carbamoyl, optionally substituted N--C₇ -C₁₅aralkylcarbamoyl, optionally substituted N,N-di-C₁ -C₁₀alkylaminocarbonyl, optionally substituted N--C₃ -C₁₀cycloalkylcarbamoyl, optionally substituted C₁ -C₁₀ alkoxycarbonyl,optionally substituted C₆ -C₁₅ aryloxycarbonyl, optionally substitutedC₇ -C₁₅ aralkyloxycarbonyl, optionally substituted C₁ -C₁₅heteroaromatic thiocarbonyl having at least one hetero atom selectedfrom the group consisting of nitrogen, oxygen, and sulfur atoms,optionally substituted C₂ -C₁₅ saturated heterocyclic thiocarbonylhaving at least one hetero atom selected from the group consisting ofnitrogen, oxygen, and sulfur atoms, or optionally substituted N--C₁ -C₁₀alkyl-thiocarbamoyl; and R³ representsa hydrogen atom, a hydroxyl group,optionally substituted C₁ -C₁₀ alkyloxy, optionally substituted C₂ -C₁₀alkenyloxy, optionally substituted C₂ -C₁₀ alkynyloxy, optionallysubstituted C₃ -C₁₀ cycloalkyloxy, optionally substituted C₇ -C₁₅aralkyloxy, optionally substituted C₁ -C₁₀ alkylcarbonyloxy, optionallysubstituted C₂ -C₁₀ alkenylcarbonyloxy, optionally substituted C₂ -C₁₀alkynylcarbonyloxy, optionally substituted C₃ -C₁₀cycloalkylcarbonyloxy, optionally substituted C₇ -C₁₅ aromatic acyloxy,optionally substituted C₇ -C₁₅ aralkylcarbonyloxy, optionallysubstituted C₁ -C₁₀ alkylthio, optionally substituted C₂ -C₁₀alkenylthio, optionally substituted C₂ -C₁₀ alkynylthio, optionallysubstituted C₃ -C₁₀ cycloalkylthio, optionally substituted C₆ -C₁₅arylthio, or optionally substituted C₇ -C₁₅ aralkylthio.
 2. The compoundor pharmaceutically acceptable salt thereof according to claim 1,whereinR¹ representsoptionally substituted C₁ -C₁₀ alkyl or optionallysubstituted C₇ -C₁₅ aralkyl; R² representsa hydrogen atom, optionallysubstituted C₁ -C₁₀ alkylcarbonyl, optionally substituted C₃ -C₁₀cycloalkylcarbonyl, optionally substituted C₇ -C₁₅ aromatic acyl,optionally substituted C₂ -C₁₅ heteroaromatic acyl having at least onehetero atom selected from the group consisting of nitrogen, oxygen, andsulfur atoms, optionally substituted C₃ -C₁₅ saturated heterocyclic acylhaving at least one hetero atom selected from the group consisting ofnitrogen, oxygen, and sulfur atoms, optionally substituted C₁ -C₁₀alkyl, optionally substituted C₂ -C₁₀ alkenyl, optionally substituted C₇-C₁₅ aralkyl, carbamoyl, optionally substituted N--C₁ -C₁₀alkylcarbamoyl, optionally substituted N--C₆ -C₁₅ aromatic carbamoyl,optionally substituted N--C₇ -C₁₅ aralkylcarbamoyl, optionallysubstituted N,N-di-C₁ -C₁₀ alkylaminocarbonyl, optionally substitutedN--C₃ -C₁₀ cycloalkylcarbamoyl, optionally substituted C₁ -C₁₀alkoxycarbonyl, optionally substituted C₆ -C₁₅ aryloxycarbonyl,optionally substituted C₁ -C₁₅ heteroaromatic thiocarbonyl having atleast one hetero atom selected from the group consisting of nitrogen,oxygen, and sulfur atoms, optionally substituted C₂ -C₁₅ saturatedheterocyclic thiocarbonyl having at least one hetero atom selected fromthe group consisting of nitrogen, oxygen, and sulfur atoms, oroptionally substituted N--C₁ -C₁₀ alkyl-thiocarbamoyl; and R³representsa hydrogen atom, a hydroxyl group, optionally substituted C₁-C₁₀ alkyloxy, optionally substituted C₁ -C₁₀ alkylcarbonyloxy,optionally substituted C₁ -C₁₀ alkylthio, or optionally substituted C₆-C₁₅ arylthio.
 3. The compound or pharmaceutically acceptable saltthereof according to claim 1, whereinR¹ representsC₁ -C₁₀ alkyl or C₇-C₁₅ aralkyl optionally substituted by C₁ -C₆ alkoxy; R² representsahydrogen atom, C₁ -C₁₀ alkylcarbonyl, C₃ -C₁₅ cycloalkylcarbonyl, C₆-C₁₅ aromatic acyl optionally substituted by C₁ -C₆ alkoxy or nitro, C₂-C₁₅ heteroaromatic acyl having at least one hetero atom selected fromthe group consisting of nitrogen, oxygen, and sulfur atoms, C₃ -C₁₅saturated heterocyclic acyl, having at least one hetero atom selectedfrom the group consisting of nitrogen, oxygen, and sulfur atoms,optionally substituted by C₁ -C₆ alkyl or C₁ -C₆ alkoxy-C₁ -C₆ alkyl, C₁-C₁₀ alkyl optionally substituted by C₃ -C₁₅ cycloalkyl or hydroxyl, C₂-C₁₀ alkenyl optionally substituted by phenyl, C₇ -C₁₅ aralkyloptionally substituted by C₁ -C₆ alkoxy, carbamoyl, N--C₁ -C₁₀alkylcarbamoyl with hydrogen atom(s) in the alkyl being optionallysubstituted by a hydroxyl group, N--C₆ -C₁₅ aromatic carbamoyl, N--C₇-C₁₅ aralkylcarbamoyl, N,N-di-C₁ -C₁₀ alkylaminocarbonyl, N--C₃ -C₁₀cycloalkylcarbamoyl, C₁ -C₁₀ alkoxycarbonyl, C₆ -C₁₅ aryloxycarbonyl, C₁-C₁₅ heteroaromatic thiocarbonyl having at least one nitrogen atom, C₂-C₁₅ saturated heterocyclic thiocarbonyl having at least one nitrogenatom, or N--C₁ -C₁₀ alkyl-thiocarbamoyl; and R³ representsa hydrogenatom, a hydroxyl group, C₁ -C₁₀ alkyloxy optionally substituted by C₃-C₁₀ cycloalkyl, C₁ -C₁₀ alkylcarbonyloxy, C₁ -C₁₀ alkylthio, or C₆ -C₁₅arylthio.
 4. The compound or pharmaceutically acceptable salt thereofaccording to claim 1, whereinR¹ representsC₁ -C₆ alkyl or benzyloptionally substituted by C₁ -C₆ alkoxy; R² representsa hydrogen atom,C₁ -C₆ alkylcarbonyl, C₃ -C₇ cycloalkylcarbonyl, benzoyl optionallysubstituted by C₁ -C₆ alkoxy or nitro, five- or six-memberedheteroaromatic acyl having one or two nitrogen, oxygen, or sulfur atoms,five- or six-membered heteroaromatic acyl having nitrogen and sulfuratoms, five- or six-membered saturated heterocyclic acyl having a oxygenor sulfur atom, C₁ -C₆ alkyl optionally substituted by C₃ -C₇ cycloalkylor hydroxy, C₂ -C₆ alkenyl optionally substituted by phenyl, benzyloptionally substituted by C₁ -C₆ alkoxy, carbamoyl, N--C₁ -C₆alkylcarbamoyl with hydrogen atom(s) in the alkyl being optionallysubstituted by a hydroxyl group, N-phenylcarbamoyl, N-benzylcarbamoyl,N,N-di-C₁ -C₆ alkylaminocarbonyl, N--C₃ -C₇ cycloalkylcarbamoyl, C₁ -C₆alkoxycarbonyl, phenyloxycarbonyl, pyrimidylthiocarbonyl,pyrrolidylthiocarbonyl, or N--C₁ -C₆ alkyl-thiocarbamoyl; and R³representsa hydrogen atom, a hydroxyl group, C₁ -C₆ alkyloxy optionallysubstituted by C₃ -C₇ cycloalkyl, C₁ -C₆ alkylcarbonyloxy, C₁ -C₆alkylthio, or phenylthio.
 5. A pharmaceutical composition comprising asan active ingredient the compound according to any one of claims 1 to 4.6. The pharmaceutical composition according to claim 5, which is atherapeutic or prophylactic agent for progesterone-related diseases, oran abortifacient or a contraceptive.
 7. The pharmaceutical compositionaccording to claim 5, which is a carcinostatic agent for breast canceror ovarian cancer, a therapeutic agent for hysteromyoma, endometriosis,meningioma, or myeloma, a therapeutic or prophylactic agent forosteoporosis or climacteric disturbance, an abortifacient, or an oralcontraceptive pill.
 8. A method for treating or preventingprogesterone-related diseases, for having an abortion, or for orallypreventing conception, wherein the compound according to any one ofclaims 1 to 4 is administered to a mammal including a human being.
 9. Amethod for treating or preventing breast cancer, ovarian cancer,hysteromyoma, endometriosis, meningioma, myeloma, osteoporosis, orclimacteric disturbance, for having an abortion, or for orallypreventing conception, wherein the compound according to any one ofclaims 1 to 4 is administered to a mammal including a human being.
 10. Acompound represented by the following formula (II) or a pharmaceuticallyacceptable salt thereof: ##STR268## wherein R¹ representsa hydrogenatom, optionally substituted C₁ -C₁₀ alkyl, optionally substituted C₂-C₁₀ alkenyl, optionally substituted C₂ -C₁₀ alkynyl, optionallysubstituted C₃ -C₁₀ cycloalkyl, or optionally substituted C₇ -C₁₅aralkyl.